Isoquine and Related Amodiaquine Analogues: A New Generation of Improved 4-Aminoquinoline Antimalarials
Identifieur interne : 000743 ( Istex/Corpus ); précédent : 000742; suivant : 000744Isoquine and Related Amodiaquine Analogues: A New Generation of Improved 4-Aminoquinoline Antimalarials
Auteurs : Paul M. O'Neill ; Amira Mukhtar ; Paul A. Stocks ; Laura E. Randle ; Stephen Hindley ; Stephen A. Ward ; Richard C. Storr ; Jamie F. Bickley ; Ian A. O'Neil ; James L. Maggs ; Ruth H. Hughes ; Peter A. Winstanley ; Patrick G. Bray ; B. Kevin ParkSource :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2003.
Abstract
Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3‘ hydroxyl and the 4‘ Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC50 = 6.01 nM ± 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED50 activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.
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DOI: 10.1021/jm030796n
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<author><name sortKey="O Neill, Paul M" sort="O Neill, Paul M" uniqKey="O Neill P" first="Paul M." last="O'Neill">Paul M. O'Neill</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</mods:affiliation>
</affiliation>
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<author><name sortKey="Mukhtar, Amira" sort="Mukhtar, Amira" uniqKey="Mukhtar A" first="Amira" last="Mukhtar">Amira Mukhtar</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Stocks, Paul A" sort="Stocks, Paul A" uniqKey="Stocks P" first="Paul A." last="Stocks">Paul A. Stocks</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Randle, Laura E" sort="Randle, Laura E" uniqKey="Randle L" first="Laura E." last="Randle">Laura E. Randle</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Hindley, Stephen" sort="Hindley, Stephen" uniqKey="Hindley S" first="Stephen" last="Hindley">Stephen Hindley</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Ward, Stephen A" sort="Ward, Stephen A" uniqKey="Ward S" first="Stephen A." last="Ward">Stephen A. Ward</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Molecular and Biochemical Parasitology Group.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Storr, Richard C" sort="Storr, Richard C" uniqKey="Storr R" first="Richard C." last="Storr">Richard C. Storr</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Bickley, Jamie F" sort="Bickley, Jamie F" uniqKey="Bickley J" first="Jamie F." last="Bickley">Jamie F. Bickley</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="O Neil, Ian A" sort="O Neil, Ian A" uniqKey="O Neil I" first="Ian A." last="O'Neil">Ian A. O'Neil</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Maggs, James L" sort="Maggs, James L" uniqKey="Maggs J" first="James L." last="Maggs">James L. Maggs</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Hughes, Ruth H" sort="Hughes, Ruth H" uniqKey="Hughes R" first="Ruth H." last="Hughes">Ruth H. Hughes</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Molecular and Biochemical Parasitology Group.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Winstanley, Peter A" sort="Winstanley, Peter A" uniqKey="Winstanley P" first="Peter A." last="Winstanley">Peter A. Winstanley</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Bray, Patrick G" sort="Bray, Patrick G" uniqKey="Bray P" first="Patrick G." last="Bray">Patrick G. Bray</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Molecular and Biochemical Parasitology Group.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Park, B Kevin" sort="Park, B Kevin" uniqKey="Park B" first="B. Kevin" last="Park">B. Kevin Park</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</mods:affiliation>
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<sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Isoquine and Related Amodiaquine Analogues: A New Generation of Improved
4-Aminoquinoline Antimalarials</title>
<author><name sortKey="O Neill, Paul M" sort="O Neill, Paul M" uniqKey="O Neill P" first="Paul M." last="O'Neill">Paul M. O'Neill</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Mukhtar, Amira" sort="Mukhtar, Amira" uniqKey="Mukhtar A" first="Amira" last="Mukhtar">Amira Mukhtar</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Stocks, Paul A" sort="Stocks, Paul A" uniqKey="Stocks P" first="Paul A." last="Stocks">Paul A. Stocks</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Randle, Laura E" sort="Randle, Laura E" uniqKey="Randle L" first="Laura E." last="Randle">Laura E. Randle</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Hindley, Stephen" sort="Hindley, Stephen" uniqKey="Hindley S" first="Stephen" last="Hindley">Stephen Hindley</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Ward, Stephen A" sort="Ward, Stephen A" uniqKey="Ward S" first="Stephen A." last="Ward">Stephen A. Ward</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Molecular and Biochemical Parasitology Group.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Storr, Richard C" sort="Storr, Richard C" uniqKey="Storr R" first="Richard C." last="Storr">Richard C. Storr</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Bickley, Jamie F" sort="Bickley, Jamie F" uniqKey="Bickley J" first="Jamie F." last="Bickley">Jamie F. Bickley</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="O Neil, Ian A" sort="O Neil, Ian A" uniqKey="O Neil I" first="Ian A." last="O'Neil">Ian A. O'Neil</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Chemistry.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Maggs, James L" sort="Maggs, James L" uniqKey="Maggs J" first="James L." last="Maggs">James L. Maggs</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Hughes, Ruth H" sort="Hughes, Ruth H" uniqKey="Hughes R" first="Ruth H." last="Hughes">Ruth H. Hughes</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Molecular and Biochemical Parasitology Group.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Winstanley, Peter A" sort="Winstanley, Peter A" uniqKey="Winstanley P" first="Peter A." last="Winstanley">Peter A. Winstanley</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Bray, Patrick G" sort="Bray, Patrick G" uniqKey="Bray P" first="Patrick G." last="Bray">Patrick G. Bray</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Molecular and Biochemical Parasitology Group.</mods:affiliation>
</affiliation>
</author>
<author><name sortKey="Park, B Kevin" sort="Park, B Kevin" uniqKey="Park B" first="B. Kevin" last="Park">B. Kevin Park</name>
<affiliation><mods:affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Department of Pharmacology and Therapeutics.</mods:affiliation>
</affiliation>
<affiliation><mods:affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</mods:affiliation>
</affiliation>
</author>
</analytic>
<monogr></monogr>
<series><title level="j" type="main">Journal of Medicinal Chemistry</title>
<title level="j" type="abbrev">J. Med. Chem.</title>
<idno type="ISSN">0022-2623</idno>
<idno type="eISSN">1520-4804</idno>
<imprint><publisher>American Chemical Society</publisher>
<date type="e-published" when="2003-09-30">2003</date>
<date when="2003-11-06">2003</date>
<biblScope unit="vol">46</biblScope>
<biblScope unit="issue">23</biblScope>
<biblScope unit="page" from="4933">4933</biblScope>
<biblScope unit="page" to="4945">4945</biblScope>
</imprint>
<idno type="ISSN">0022-2623</idno>
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<front><div type="abstract">Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3‘ hydroxyl and the 4‘ Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC50 = 6.01 nM ± 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED50 activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.</div>
</front>
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<author><json:item><name>O'NEILL Paul M.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Chemistry.</json:string>
<json:string>Department of Pharmacology and Therapeutics.</json:string>
<json:string>Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</json:string>
</affiliations>
</json:item>
<json:item><name>MUKHTAR Amira</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Chemistry.</json:string>
</affiliations>
</json:item>
<json:item><name>STOCKS Paul A.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Chemistry.</json:string>
</affiliations>
</json:item>
<json:item><name>RANDLE Laura E.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Pharmacology and Therapeutics.</json:string>
</affiliations>
</json:item>
<json:item><name>HINDLEY Stephen</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Chemistry.</json:string>
</affiliations>
</json:item>
<json:item><name>WARD Stephen A.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Molecular and Biochemical Parasitology Group.</json:string>
<json:string>Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</json:string>
</affiliations>
</json:item>
<json:item><name>STORR Richard C.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Chemistry.</json:string>
</affiliations>
</json:item>
<json:item><name>BICKLEY Jamie F.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Chemistry.</json:string>
</affiliations>
</json:item>
<json:item><name>O'NEIL Ian A.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Chemistry.</json:string>
</affiliations>
</json:item>
<json:item><name>MAGGS James L.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Pharmacology and Therapeutics.</json:string>
</affiliations>
</json:item>
<json:item><name>HUGHES Ruth H.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Molecular and Biochemical Parasitology Group.</json:string>
</affiliations>
</json:item>
<json:item><name>WINSTANLEY Peter A.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Pharmacology and Therapeutics.</json:string>
</affiliations>
</json:item>
<json:item><name>BRAY Patrick G.</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Molecular and Biochemical Parasitology Group.</json:string>
</affiliations>
</json:item>
<json:item><name>PARK B. Kevin</name>
<affiliations><json:string>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</json:string>
<json:string>Department of Pharmacology and Therapeutics.</json:string>
<json:string>Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</json:string>
</affiliations>
</json:item>
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<abstract>Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3‘ hydroxyl and the 4‘ Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC50 = 6.01 nM ± 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED50 activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.</abstract>
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4-Aminoquinoline Antimalarials</title>
<author xml:id="author-0000" role="corresp"><persName><surname>O'Neill</surname>
<forename type="first">Paul M.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>†</ref>
<p>
Department of Chemistry.</p>
</note>
<note place="foot"><ref>‡</ref>
<p>
Department of Pharmacology and Therapeutics.</p>
</note>
<affiliation role="corresp"> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553. Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@ liv.ac.uk.</affiliation>
</author>
<author xml:id="author-0001"><persName><surname>Mukhtar</surname>
<forename type="first">Amira</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>†</ref>
<p>
Department of Chemistry.</p>
</note>
</author>
<author xml:id="author-0002"><persName><surname>Stocks</surname>
<forename type="first">Paul A.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>†</ref>
<p>
Department of Chemistry.</p>
</note>
</author>
<author xml:id="author-0003"><persName><surname>Randle</surname>
<forename type="first">Laura E.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>‡</ref>
<p>
Department of Pharmacology and Therapeutics.</p>
</note>
</author>
<author xml:id="author-0004"><persName><surname>Hindley</surname>
<forename type="first">Stephen</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>†</ref>
<p>
Department of Chemistry.</p>
</note>
</author>
<author xml:id="author-0005" role="corresp"><persName><surname>Ward</surname>
<forename type="first">Stephen A.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>§</ref>
<p>
Molecular and Biochemical Parasitology Group.</p>
</note>
<affiliation role="corresp"> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553. Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@ liv.ac.uk.</affiliation>
</author>
<author xml:id="author-0006"><persName><surname>Storr</surname>
<forename type="first">Richard C.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>†</ref>
<p>
Department of Chemistry.</p>
</note>
</author>
<author xml:id="author-0007"><persName><surname>Bickley</surname>
<forename type="first">Jamie F.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>†</ref>
<p>
Department of Chemistry.</p>
</note>
</author>
<author xml:id="author-0008"><persName><surname>O'Neil</surname>
<forename type="first">Ian A.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>†</ref>
<p>
Department of Chemistry.</p>
</note>
</author>
<author xml:id="author-0009"><persName><surname>Maggs</surname>
<forename type="first">James L.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>‡</ref>
<p>
Department of Pharmacology and Therapeutics.</p>
</note>
</author>
<author xml:id="author-0010"><persName><surname>Hughes</surname>
<forename type="first">Ruth H.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>§</ref>
<p>
Molecular and Biochemical Parasitology Group.</p>
</note>
</author>
<author xml:id="author-0011"><persName><surname>Winstanley</surname>
<forename type="first">Peter A.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>‡</ref>
<p>
Department of Pharmacology and Therapeutics.</p>
</note>
</author>
<author xml:id="author-0012"><persName><surname>Bray</surname>
<forename type="first">Patrick G.</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>§</ref>
<p>
Molecular and Biochemical Parasitology Group.</p>
</note>
</author>
<author xml:id="author-0013" role="corresp"><persName><surname>Park</surname>
<forename type="first">B. Kevin</forename>
</persName>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</affiliation>
<note place="foot"><ref>‡</ref>
<p>
Department of Pharmacology and Therapeutics.</p>
</note>
<affiliation role="corresp"> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553. Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@ liv.ac.uk.</affiliation>
</author>
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<idno type="pISSN">0022-2623</idno>
<idno type="eISSN">1520-4804</idno>
<imprint><publisher>American Chemical Society</publisher>
<date type="e-published" when="2003-09-30">2003</date>
<date when="2003-11-06">2003</date>
<biblScope unit="vol">46</biblScope>
<biblScope unit="issue">23</biblScope>
<biblScope unit="page" from="4933">4933</biblScope>
<biblScope unit="page" to="4945">4945</biblScope>
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<profileDesc><abstract><graphic url="jm030796nn00001.tif"></graphic>
<p>Amodiaquine (AQ) (<hi rend="bold">2</hi>
) is a 4-aminoquinoline antimalarial that can cause adverse side effects
including agranulocytosis and liver damage. The observed drug toxicity is believed to involve
the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can
bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that
interchange of the 3‘ hydroxyl and the 4‘ Mannich side-chain function of amodiaquine would
provide a new series of analogues that cannot form toxic quinoneimine metabolites via
cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant
K1 and sensitive HB3 strains of <hi rend="italic">Plasmodium falciparum </hi>
in vitro. Several analogues displayed
potent antimalarial activity against both strains. On the basis of the results of in vitro testing,
isoquine (ISQ1 (<hi rend="bold">3a</hi>
)) (IC<hi rend="subscript">50</hi>
= 6.01 nM ± 8.0 versus K1 strain), the direct isomer of amodiaquine,
was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of
isoquine was translated into excellent oral in vivo ED<hi rend="subscript">50</hi>
activity of 1.6 and 3.7 mg/kg against
the <hi rend="italic">P. </hi>
<hi rend="italic">yoelii</hi>
NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism
studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as
evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to
amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (<hi rend="bold">3a</hi>
)) represents a new
second generation lead worthy of further investigation as a cost-effective and potentially safer
alternative to amodiaquine.
</p>
</abstract>
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<istex:document><article article-type="research-article" specific-use="acs2jats-1.1.23" dtd-version="1.1d1"><front><journal-meta><journal-id journal-id-type="acspubs">jm</journal-id>
<journal-id journal-id-type="coden">jmcmar</journal-id>
<journal-title-group><journal-title>Journal of Medicinal Chemistry</journal-title>
<abbrev-journal-title>J. Med. Chem.</abbrev-journal-title>
</journal-title-group>
<issn pub-type="ppub">0022-2623</issn>
<issn pub-type="epub">1520-4804</issn>
<publisher><publisher-name>American Chemical Society</publisher-name>
</publisher>
<self-uri>pubs.acs.org/jmc</self-uri>
</journal-meta>
<article-meta><article-id pub-id-type="doi">10.1021/jm030796n</article-id>
<article-categories><subj-group subj-group-type="document-type-name"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Isoquine and Related Amodiaquine Analogues: A New Generation of Improved
4-Aminoquinoline Antimalarials</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name name-style="western"><surname>O'Neill</surname>
<given-names>Paul M.</given-names>
</name>
<xref rid="jm030796nAF1">*</xref>
<xref rid="jm030796nAF2"><sup>†</sup>
</xref>
<xref rid="jm030796nAF3"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Mukhtar</surname>
<given-names>Amira</given-names>
</name>
<xref rid="jm030796nAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Stocks</surname>
<given-names>Paul A.</given-names>
</name>
<xref rid="jm030796nAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Randle</surname>
<given-names>Laura E.</given-names>
</name>
<xref rid="jm030796nAF3"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Hindley</surname>
<given-names>Stephen</given-names>
</name>
<xref rid="jm030796nAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name name-style="western"><surname>Ward</surname>
<given-names>Stephen A.</given-names>
</name>
<xref rid="jm030796nAF1">*</xref>
<xref rid="jm030796nAF4"><sup>§</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Storr</surname>
<given-names>Richard C.</given-names>
</name>
<xref rid="jm030796nAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Bickley</surname>
<given-names>Jamie F.</given-names>
</name>
<xref rid="jm030796nAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>O'Neil</surname>
<given-names>Ian A.</given-names>
</name>
<xref rid="jm030796nAF2"><sup>†</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Maggs</surname>
<given-names>James L.</given-names>
</name>
<xref rid="jm030796nAF3"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Hughes</surname>
<given-names>Ruth H.</given-names>
</name>
<xref rid="jm030796nAF4"><sup>§</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Winstanley</surname>
<given-names>Peter A.</given-names>
</name>
<xref rid="jm030796nAF3"><sup>‡</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name name-style="western"><surname>Bray</surname>
<given-names>Patrick G.</given-names>
</name>
<xref rid="jm030796nAF4"><sup>§</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name name-style="western"><surname>Park</surname>
<given-names>B. Kevin</given-names>
</name>
<xref rid="jm030796nAF1">*</xref>
<xref rid="jm030796nAF3"><sup>‡</sup>
</xref>
</contrib>
<aff>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department of
Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and Biochemical
Parasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK
</aff>
</contrib-group>
<author-notes><corresp id="jm030796nAF1">
Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.
Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone:
0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@
liv.ac.uk.
</corresp>
<fn id="jm030796nAF2"><label>†</label>
<p>
Department of Chemistry.</p>
</fn>
<fn id="jm030796nAF3"><label>‡</label>
<p>
Department of Pharmacology and Therapeutics.</p>
</fn>
<fn id="jm030796nAF4"><label>§</label>
<p>
Molecular and Biochemical Parasitology Group.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>30</day>
<month>09</month>
<year>2003</year>
</pub-date>
<pub-date pub-type="ppub"><day>06</day>
<month>11</month>
<year>2003</year>
</pub-date>
<volume>46</volume>
<issue>23</issue>
<fpage>4933</fpage>
<lpage>4945</lpage>
<supplementary-material xlink:href="jm030796n_s.pdf" orientation="portrait" position="float"></supplementary-material>
<history><date date-type="received"><day>03</day>
<month>02</month>
<year>2003</year>
</date>
<date date-type="asap"><day>30</day>
<month>09</month>
<year>2003</year>
</date>
<date date-type="issue-pub"><day>06</day>
<month>11</month>
<year>2003</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2003 American Chemical Society</copyright-statement>
<copyright-year>2003</copyright-year>
<copyright-holder>American Chemical Society</copyright-holder>
</permissions>
<abstract><graphic content-type="abstract-graphic" xlink:href="jm030796nn00001.tif" orientation="portrait" position="float"></graphic>
<p>Amodiaquine (AQ) (<bold>2</bold>
) is a 4-aminoquinoline antimalarial that can cause adverse side effects
including agranulocytosis and liver damage. The observed drug toxicity is believed to involve
the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can
bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that
interchange of the 3‘ hydroxyl and the 4‘ Mannich side-chain function of amodiaquine would
provide a new series of analogues that cannot form toxic quinoneimine metabolites via
cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant
K1 and sensitive HB3 strains of <italic toggle="yes">Plasmodium falciparum </italic>
in vitro. Several analogues displayed
potent antimalarial activity against both strains. On the basis of the results of in vitro testing,
isoquine (ISQ1 (<bold>3a</bold>
)) (IC<sub>50</sub>
= 6.01 nM ± 8.0 versus K1 strain), the direct isomer of amodiaquine,
was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of
isoquine was translated into excellent oral in vivo ED<sub>50</sub>
activity of 1.6 and 3.7 mg/kg against
the <italic toggle="yes">P. </italic>
<italic toggle="yes">yoelii</italic>
NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism
studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as
evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to
amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (<bold>3a</bold>
)) represents a new
second generation lead worthy of further investigation as a cost-effective and potentially safer
alternative to amodiaquine.
</p>
</abstract>
<custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name>
<meta-value>jm030796n</meta-value>
</custom-meta>
</custom-meta-group>
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</front>
<body><sec id="d7e317"><title>Introduction</title>
<p>Resistance to chloroquine (<bold>1</bold>
) (CQ) in <italic toggle="yes">Plasmodium
falciparum </italic>
malaria has become a major health concern
of the developing world. This resistance has prompted
a reexamination of the pharmacology of alternative
antimalarials that may be effective against resistant
strains.<named-content content-type="bibref-group"><xref rid="jm030796nb00001" ref-type="bibr"></xref>
,<xref rid="jm030796nb00002" ref-type="bibr"></xref>
</named-content>
Amodiaquine (<bold>2</bold>
) (AQ) is a 4-aminoquinoline
antimalarial which is effective against many chloroquine-resistant strains of <italic toggle="yes">P. falciparum</italic>
(Figure <xref rid="jm030796nf00001"></xref>
).
However, clinical use of AQ has been severely restricted
because of associations with hepatotoxicity and agranulocytosis.<named-content content-type="bibref-group"><xref rid="jm030796nb00003" ref-type="bibr"></xref>
,<xref rid="jm030796nb00004" ref-type="bibr"></xref>
</named-content>
<fig id="jm030796nf00001" position="float" orientation="portrait"><label>1</label>
<caption><p>Structures of chloroquine and amodiaquine.</p>
</caption>
<graphic xlink:href="jm030796nf00001.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
<p>Paracetamol (4-hydroxyacetanilide) contains a <italic toggle="yes">p</italic>
-hydroxyanilino moiety, which is believed to undergo
P-450-catalyzed oxidation to a chemically reactive quinoneimine (Scheme <xref rid="jm030796nh00001"></xref>
). Amodiaquine also contains this
functionality and might be expected to undergo enzymic
oxidation to a reactive metabolite. Studies in this
laboratory have shown that in the rat amodiaquine is
excreted in bile exclusively as the 5‘ thioether conjugates
(glutathione and cysteinyl).<xref rid="jm030796nb00005" ref-type="bibr"></xref>
This observation indicates
that the parent drug undergoes extensive bioactivation
in vivo to form amodiaquine quinoneimine (AQQI) or
semiquinoneimine (AQSQI) with subsequent conjugate
addition of glutathione <sup>6</sup>
<fig id="jm030796nh00001" position="float" fig-type="scheme" orientation="portrait"><label>1</label>
<caption><p>Bioactivation of Amodiaquine and Paracetamol to Toxic Quinoneimines by P450</p>
</caption>
<graphic xlink:href="jm030796nh00001.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
<p>Formation of one of these reactive species in vivo and
subsequent binding to cellular macromolecules could
affect cell function either directly or by immunological
mechanisms. Indeed IgG antibodies, which recognize the
5‘-cysteinyl group, have been detected in patients with
adverse reactions to amodiaquine.<xref rid="jm030796nb00007" ref-type="bibr"></xref>
In the case of paracetamol it has been shown that introduction of fluorine
into the aromatic nucleus increases the oxidation potential of the molecule and thereby blocks the in vivo
oxidation of the molecule to a cytotoxic quinoneimine.<xref rid="jm030796nb00008" ref-type="bibr"></xref>
Further studies by our group demonstrated that, in a
manner similar to paracetamol, the incorporation of
fluorine atoms into the 4-hydroxyanilino side-chain of
amodiaquine produces compounds with greater oxidative and metabolic stability.<xref rid="jm030796nb00009" ref-type="bibr"></xref>
From this earlier work,
we demonstrated that the 4‘-hydroxyl group could be
replaced with a 4‘-fluorine atom to produce an amodiaquine analogue, fluoroamodiaquine, with antimalarial
activity in the low nanomolar range. Despite these
promising observations, activity at the level of the
parent drug amodiaquine was never achieved with the
fluorinated derivatives and, on the basis of cost considerations, it was decided that an alternative approach
to producing more metabolically robust analogues,
retaining the key pharmacophoric groups, should be
sought.
</p>
<p>From our previous SAR work,<named-content content-type="bibref-group"><xref rid="jm030796nb00010" ref-type="bibr"></xref>
,<xref rid="jm030796nb00011" ref-type="bibr"></xref>
</named-content>
we have noted that
in the amodiaquine and tebuquine series of 4-aminoquinoline analogues, the presence of the 4‘ hydroxyl
group within the aromatic ring imparts greater inherent
antimalarial activity against chloroquine resistant parasites than the corresponding deoxo analogues. Interchange of the hydroxyl group and the Mannich side-chain provides a means of preventing oxidation to toxic
metabolites while retaining possible important bonding
interactions with the aromatic hydroxyl function. In this
paper, we will describe the synthesis, antimalarial
activity, and metabolism of the prototype isoquine (<bold>3a</bold>
,
ISQ 1), an amodiaquine regioisomer that cannot form
toxic metabolites by simple oxidation and which is
potent against chloroquine resistant parasites in vitro
(Scheme <xref rid="jm030796nh00002"></xref>
). The antimalarial activity of isoquine (<bold>3a</bold>
,
ISQ 1) will be compared with nine other analogues in
this series (Chart <xref rid="jm030796nc00001"></xref>
, <bold>4a</bold>
−<bold>12a</bold>
). Apart from an excellent
antiparasitic profile, isoquine and its side-chain analogues are extremely cheap antimalarials to synthesize
and on the basis of initial data reported in this paper,
may represent new leads for development of a safe,
cheap, affordable, and effective antimalarial for both
prophylaxis and treatment of malaria.
<fig id="jm030796nh00002" position="float" fig-type="scheme" orientation="portrait"><label>2</label>
<caption><p>Redesign of Amodiaquine</p>
</caption>
<graphic xlink:href="jm030796nh00002.tif" position="float" orientation="portrait"></graphic>
</fig>
<fig id="jm030796nc00001" position="float" fig-type="chart" orientation="portrait"><label>1</label>
<caption><p>Isoquine ISQ1 (<bold>3a</bold>
) and Analogues <bold>4a</bold>
−<bold>12a</bold>
</p>
</caption>
<graphic xlink:href="jm030796nc00001.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
</sec>
<sec id="d7e427"><title>Chemistry</title>
<p>The preparation of isoquine and its analogues involves
a two-step procedure from commercially available starting materials according to a method originally utilized
by Burkhalter and co-workers (Scheme <xref rid="jm030796nh00003"></xref>
).<xref rid="jm030796nb00012" ref-type="bibr"></xref>
Thus, step
1 involves a Mannich reaction of the commercially
available 3-hydroxyacetanilide to provide the Mannich
product in yields ranging from 50 to 90% (Table <xref rid="jm030796nt00001"></xref>
).
Stage 2 of the sequence involves hydrolysis of the
amide function to provide the corresponding Mannich-substituted 3-aminophenol that is subsequently coupled
with 4,7-dichloroquinoline to provide target molecules shown in Chart <xref rid="jm030796nc00001"></xref>
. The main difference between
the synthesis of this isomeric series and the amodiaquine analogues we have previously prepared is that
after amide hydrolysis, the reaction should not be
buffered to pH = 6. The intermediate 3-aminophenols
have been shown to be quite unstable at neutral pH
but are sufficiently nucleophilic to couple with 4,7-dichloroquinoline at lower pHs, i.e., after hydrolysis of
the amide, the sequential reaction can be carried out
in ethanolic solvent by addition of 4,7-
dichloroquinoline.<xref rid="jm030796nb00013" ref-type="bibr"></xref>
For purification, analogues were chromatographed as their hydrochloride salts using methanol/dichloromethane (10−20% MeOH/ dichloromethane) as
eluent. The free bases could be conveniently obtained
by dissolving pure columned solid hydrochloride product
in distilled water and adding saturated sodium bicarbonate solution. The precipitated free base could then
be dried and recrystallized from either 2-propanol or
methanol. Compounds were analyzed by HPLC and full
spectroscopic details are included in the Experimental
Section. For ISQ 1 and its pyrrolidinyl analogue (<bold>8a</bold>
),
X-ray crystallography studies demonstrate that there
is an internal hydrogen bond between the hydroxyl
function (OH as donor) and the side-chain nitrogen
(Figure <xref rid="jm030796nf00002"></xref>
). This may lead to a subtle effect on the p<italic toggle="yes">K</italic>
<sub>a</sub>
of the side-chain Mannich nitrogen atom and a reduction in basicity.
<fig id="jm030796nh00003" position="float" fig-type="scheme" orientation="portrait"><label>3</label>
<caption><p>Synthesis of Analogues<bold>3</bold>
<bold>a</bold>
−<bold>12</bold>
<bold>a</bold>
</p>
</caption>
<graphic xlink:href="jm030796nh00003.tif" position="float" orientation="portrait"></graphic>
</fig>
<fig id="jm030796nf00002" position="float" orientation="portrait"><label>2</label>
<caption><p>X-ray cystal structures of ISQ-1 (<bold>3a</bold>
) and <bold>8a</bold>
.</p>
</caption>
<graphic xlink:href="jm030796nf00002.tif" position="float" orientation="portrait"></graphic>
</fig>
<table-wrap id="jm030796nt00001" position="float" orientation="portrait"><label>1</label>
<caption><p>Yields for the Synthesis of Isoquine (<bold>3</bold>
<bold>a</bold>
) and
Analogues <bold>4</bold>
<bold>a</bold>
−<bold>12</bold>
<bold>a</bold>
</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="4"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:colspec colnum="4" colname="4"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">intermediate amide</oasis:entry>
<oasis:entry namest="2" nameend="2">yield,
%</oasis:entry>
<oasis:entry namest="3" nameend="3">product</oasis:entry>
<oasis:entry namest="4" nameend="4">yield,
%
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>3</bold>
) R<sup>1</sup>
= Et, R<sup>2</sup>
= Et
</oasis:entry>
<oasis:entry colname="2">69
</oasis:entry>
<oasis:entry colname="3">ISQ 1 (<bold>3a</bold>
) R<sup>1</sup>
= Et, R<sup>2</sup>
= Et
</oasis:entry>
<oasis:entry colname="4">71
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>4</bold>
) R<sup>1</sup>
= H, R<sup>2</sup>
= <italic toggle="yes">t</italic>
-<italic toggle="yes">B</italic>
u
</oasis:entry>
<oasis:entry colname="2">70
</oasis:entry>
<oasis:entry colname="3">(<bold>4a</bold>
) R<sup>1</sup>
= H, R<sup>2</sup>
= <italic toggle="yes">t</italic>
-<italic toggle="yes">B</italic>
u
</oasis:entry>
<oasis:entry colname="4">69
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>5</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= Me
</oasis:entry>
<oasis:entry colname="2">74
</oasis:entry>
<oasis:entry colname="3">(<bold>5a</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= Me
</oasis:entry>
<oasis:entry colname="4">69
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>6</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= <italic toggle="yes">n</italic>
-propyl
</oasis:entry>
<oasis:entry colname="2">63
</oasis:entry>
<oasis:entry colname="3">(<bold>6a</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= <italic toggle="yes">n</italic>
-propyl
</oasis:entry>
<oasis:entry colname="4">61
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>7</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= <italic toggle="yes">n</italic>
-butyl
</oasis:entry>
<oasis:entry colname="2">52
</oasis:entry>
<oasis:entry colname="3">(<bold>7a</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= <italic toggle="yes">n</italic>
-butyl
</oasis:entry>
<oasis:entry colname="4">58
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>8</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= (CH<sub>2</sub>
)<sub>4</sub>
</oasis:entry>
<oasis:entry colname="2">89
</oasis:entry>
<oasis:entry colname="3">(<bold>8a</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= (CH<sub>2</sub>
)<sub>4</sub>
</oasis:entry>
<oasis:entry colname="4">80
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>9</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= (CH<sub>2</sub>
)<sub>2</sub>
O(CH<sub>2</sub>
)<sub>2</sub>
</oasis:entry>
<oasis:entry colname="2">72
</oasis:entry>
<oasis:entry colname="3">(<bold>9a</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= (CH<sub>2</sub>
)<sub>2</sub>
O(CH<sub>2</sub>
)<sub>2</sub>
</oasis:entry>
<oasis:entry colname="4">60
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>10</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= (CH<sub>2</sub>
)<sub>5</sub>
</oasis:entry>
<oasis:entry colname="2">80
</oasis:entry>
<oasis:entry colname="3">(<bold>10a</bold>
) R<sup>1</sup>
, R<sup>2</sup>
= (CH<sub>2</sub>
)<sub>5</sub>
</oasis:entry>
<oasis:entry colname="4">71
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>11</bold>
) R<sup>1</sup>
= H, R<sup>2</sup>
= <italic toggle="yes">i</italic>
-Pr
</oasis:entry>
<oasis:entry colname="2">51
</oasis:entry>
<oasis:entry colname="3">(<bold>11a</bold>
) R<sup>1</sup>
= H, R<sup>2</sup>
= <italic toggle="yes">i</italic>
-Pr
</oasis:entry>
<oasis:entry colname="4">67
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">(<bold>12</bold>
) R<sup>1</sup>
= H, R<sup>2</sup>
= Et
</oasis:entry>
<oasis:entry colname="2">55
</oasis:entry>
<oasis:entry colname="3">(<bold>12a</bold>
) R<sup>1</sup>
= H, R<sup>2</sup>
= Et
</oasis:entry>
<oasis:entry colname="4">68</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
</table-wrap>
</p>
<p><bold>Antimalarial Activity.</bold>
Analogues were initially
tested in vitro against the chloroquine sensitive HB3
strain and against the highly chloroquine-resistant K1
strain of <italic toggle="yes">P. falciparum </italic>
(Table <xref rid="jm030796nt00002"></xref>
). Against the HB3
chloroquine sensitive isolate, isoquine (<bold>3a</bold>
), its diphosphate salt (<bold>3b</bold>
), and compounds <bold>5a</bold>
, <bold>6a</bold>
, <bold>10a</bold>
, and <bold>12a</bold>
all express activity below 20 nM. In line with previous
SAR studies on 4-aminoquinoline analogues, the morpholinyl analogue (<bold>9a</bold>
) is a poor antimalarial with
activity close to 100 nM.<xref rid="jm030796nb00032" ref-type="bibr"></xref>
Clearly, the two most potent
compounds tested against the HB3 strain were isoquine
free base and the diphosphate salt (<bold>3b</bold>
) and the piperidinyl analogue (<bold>10a</bold>
). The most potent compound
against the chloroquine resistant strain was again the
diphosphate salt of isoquine although the free base is
also as potent as amodiaquine in this strain. Isoquine
and its salt are both about 20 times more potent than
chloroquine diphosphate. Compounds <bold>5a</bold>
, <bold>8a</bold>
, <bold>10a</bold>
, and
<bold>11a</bold>
also express excellent activity against this resistant
strain. It is clear that in addition to isoquine, compounds
<bold>5a</bold>
and <bold>10a</bold>
are additional leads worthy of further
investigation. Isoquine diphosphate was subsequently
tested in vivo against the murine <italic toggle="yes">Plasmodium yoelii</italic>
NS
strain. Data recorded in Table <xref rid="jm030796nt00003"></xref>
suggests that isoquine
has superior antimalarial activity to amodiaquine in
vivo. Indeed, by the oral route, <bold>3a</bold>
is almost three times
more potent than AQ.
<table-wrap id="jm030796nt00002" position="float" orientation="portrait"><label>2</label>
<caption><p>In Vitro Antimalarial Activities of Chloroquine, Amodiaquine, and Analogues<bold>3</bold>
<bold>a</bold>
−<bold>12</bold>
<bold>a</bold>
</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="5"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:colspec colnum="4" colname="4"></oasis:colspec>
<oasis:colspec colnum="5" colname="5"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">drug<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</oasis:entry>
<oasis:entry namest="2" nameend="2">IC<sub>50 </sub>
(nM)
HB3</oasis:entry>
<oasis:entry namest="3" nameend="3">SD ±
mean</oasis:entry>
<oasis:entry namest="4" nameend="4">IC<sub>50</sub>
(nM)
K1</oasis:entry>
<oasis:entry namest="5" nameend="5">SD ±
mean
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">chloroquine (<bold>1</bold>
)
</oasis:entry>
<oasis:entry colname="2">14.98 (6)
</oasis:entry>
<oasis:entry colname="3">3.98
</oasis:entry>
<oasis:entry colname="4">183.82 (6)
</oasis:entry>
<oasis:entry colname="5">11.13
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">amodiaquine (<bold>2</bold>
)
</oasis:entry>
<oasis:entry colname="2">9.60 (9)
</oasis:entry>
<oasis:entry colname="3">3.73
</oasis:entry>
<oasis:entry colname="4">15.08 (9)
</oasis:entry>
<oasis:entry colname="5">9.36
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">isoquine (ISQ-1) (<bold>3a</bold>
)
</oasis:entry>
<oasis:entry colname="2">12.65 (9)
</oasis:entry>
<oasis:entry colname="3">4.75
</oasis:entry>
<oasis:entry colname="4">17.63 (9)
</oasis:entry>
<oasis:entry colname="5">7.00
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">isoquine diphosphate (<bold>3b</bold>
)
</oasis:entry>
<oasis:entry colname="2">9.02 (3)
</oasis:entry>
<oasis:entry colname="3">4.06
</oasis:entry>
<oasis:entry colname="4">6.01 (3)
</oasis:entry>
<oasis:entry colname="5">8.00
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(4a)</bold>
</oasis:entry>
<oasis:entry colname="2">30.03 (3)
</oasis:entry>
<oasis:entry colname="3">17.67
</oasis:entry>
<oasis:entry colname="4">32.75 (4)
</oasis:entry>
<oasis:entry colname="5">13.16
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(5a)</bold>
</oasis:entry>
<oasis:entry colname="2">14.76 (9)
</oasis:entry>
<oasis:entry colname="3">12.30
</oasis:entry>
<oasis:entry colname="4">18.65 (9)
</oasis:entry>
<oasis:entry colname="5">9.08
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(6a)</bold>
</oasis:entry>
<oasis:entry colname="2">19.78 (9)
</oasis:entry>
<oasis:entry colname="3">15.30
</oasis:entry>
<oasis:entry colname="4">30.63 (4)
</oasis:entry>
<oasis:entry colname="5">16.53
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(7a)</bold>
</oasis:entry>
<oasis:entry colname="2">51.88 (4)
</oasis:entry>
<oasis:entry colname="3">19.77
</oasis:entry>
<oasis:entry colname="4">37.21 (4)
</oasis:entry>
<oasis:entry colname="5">12.86
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(8a)</bold>
</oasis:entry>
<oasis:entry colname="2">28.37 (4)
</oasis:entry>
<oasis:entry colname="3">9.03
</oasis:entry>
<oasis:entry colname="4">21.75 (3)
</oasis:entry>
<oasis:entry colname="5">2.65
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(9a)</bold>
</oasis:entry>
<oasis:entry colname="2">97.20 (4)
</oasis:entry>
<oasis:entry colname="3">15.31
</oasis:entry>
<oasis:entry colname="4">112.37 (4)
</oasis:entry>
<oasis:entry colname="5">36.99
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(10a)</bold>
</oasis:entry>
<oasis:entry colname="2">9.07 (4)
</oasis:entry>
<oasis:entry colname="3">0.30
</oasis:entry>
<oasis:entry colname="4">20.28 (3)
</oasis:entry>
<oasis:entry colname="5">4.99
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(11a)</bold>
</oasis:entry>
<oasis:entry colname="2">20.22 (4)
</oasis:entry>
<oasis:entry colname="3">4.34
</oasis:entry>
<oasis:entry colname="4">26.22 (4)
</oasis:entry>
<oasis:entry colname="5">8.03
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(12a)</bold>
</oasis:entry>
<oasis:entry colname="2">16.24 (4)
</oasis:entry>
<oasis:entry colname="3">11.24
</oasis:entry>
<oasis:entry colname="4">32.42 (4)
</oasis:entry>
<oasis:entry colname="5">14.70</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
Amodiaquine was tested as the hydrochloride salt, ISQ-1 and
<bold>3a</bold>
−<bold>12a</bold>
were all tested as free bases. Chloroquine was tested as
the diphosphate.</p>
</table-wrap-foot>
</table-wrap>
<table-wrap id="jm030796nt00003" position="float" orientation="portrait"><label>3</label>
<caption><p>In Vivo Antimalarial Activity of Isoquine and Amodiaquine versus<italic toggle="yes">P. </italic>
<italic toggle="yes">y</italic>
<italic toggle="yes">oelii</italic>
NS Strain in the Peters 4-Day
Test</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="3"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">compound</oasis:entry>
<oasis:entry namest="2" nameend="2">isoquine</oasis:entry>
<oasis:entry namest="3" nameend="3">amodiaquine
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">ED<sub>50</sub>
(mg/kg)
</oasis:entry>
<oasis:entry colname="2">2.65
</oasis:entry>
<oasis:entry colname="3">7.65
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">SD
</oasis:entry>
<oasis:entry colname="2">± 1.48
</oasis:entry>
<oasis:entry colname="3">± 0.35</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
Groups of male CD-1 mice (<italic toggle="yes">n</italic>
= 5 per dose group) were
inoculated by ip injection with 10<sup>6</sup>
parasitized erythrocytes in
phosphate buffered saline. Drug was administered by oral gavage
at time = 0 (equivalent to 2 h post parasite inoculation) and on
days 1, 2, and 3. Blood films were prepared from tail snips on day
4 and stained with Giemsa, and parasite density was counted
microscopically. Drug doses used were 25, 10, 3, 1, 0.3, and 0.1
mg/kg.</p>
</table-wrap-foot>
</table-wrap>
</p>
<p><bold>Metabolism Studies.</bold>
To determine whether the
side chain modifications introduced would alter the
comparative metabolic fate of metabolism, studies were
carried out in the rat. Rearrangement of the hydroxyl
and diethylamino side chains to a 1,3-aminophenol
suggest that this compound would be unable to form a
quinonimine, as it is not chemically feasible to lose two
hydrogens via the same oxidative mechanism as AQ.<xref rid="jm030796nb00014" ref-type="bibr"></xref>
</p>
<p>In addition to being capable of forming toxic metabolites, internal hydrogen bonding between the <italic toggle="yes">p</italic>
-hydroxyanilino moiety and the nitrogen of the diethylamino side chain could be responsible for preventing AQ
from undergoing the <italic toggle="yes">O</italic>
-sulfation and/or <italic toggle="yes">O</italic>
-glucuronidation experienced by other structurally related compounds.<xref rid="jm030796nb00015" ref-type="bibr"></xref>
This results in the failure of AQ to undergo
phase II detoxication. Removal of the diethylamino side
chain has been shown to allow AQ to undergo excessive
<italic toggle="yes">O</italic>
-sulfation in the rat. In the context of the present
study, we were interested to see if the 3‘-OH function
in <bold>3</bold>
would be capable of undergoing metabolic phase II
conjugation reactions.
</p>
<p>Using radiolabeled<sup>3</sup>
[H] isoquine, initial in vivo dispositional studies indicated that there is no alteration
in the rate of excretion of ISQ1 into bile and urine after
5 h compared to AQ. The main site for accumulation of
ISQ was found to be the liver, a primary target organ
for drug metabolism. 6.85% of the AQ dose remained
in the liver, 24 h after administration to rats compared
to 20.82% of the dose at 5 h. This was coupled with a
3% increase in radioactivity excreted into urine between
5 h and 24 h. Only 5.48% of the ISQ1 dose remained in
the liver after 24 h compared to 32.93% after 5 h,
suggesting almost complete clearance of the compound
at 24 h.
</p>
<p>For isoquine (<bold>3a</bold>
), during the 5h experiment, a 3-fold
increase in plasma levels compared to AQ was witnessed. This increase in plasma levels for isoquine
(0.130%, ±0.018) was significantly different to amodiaquine levels (0.05%, ±0.012 <italic toggle="yes">P</italic>
> 0.05). This observation
may be important since the blood is the primary site of
action for 4-aminoquinoline antimalarials. Using LCMS
analysis, the main circulating metabolite for isoquine
in the plasma was the parent compound, in contrast to
amodiaquine where the only metabolite detected was
the desethyl metabolite.<xref rid="jm030796nb00016" ref-type="bibr"></xref>
</p>
<p>After 5 h, 87.17% ISQ1 dose was accounted for in the
tissues, bile plasma, and urine. Similarly, 78.56% of the
AQ dose could be accounted for after 5 h. This suggests
that there are other sites for the accumulation of the
compounds which were not analyzed during this study.
Glutathione conjugates were only detected in rats
administered AQ. Evidence to support this metabolite
was found with the presence of a mercapturate metabolite in urine. In direct contrast there was no evidence
to suggest the formation of an ISQ−glutathione conjugate in the bile of rats dosed with ISQ 1. This suggests
that bioactivation has been blocked; furthermore, and
in sharp contrast to amodiaquine, there is evidence to
suggest that relocation of the phenolic OH from the 4‘
position in AQ to the 3‘ position provides a route of
metabolic escape. LCMS analysis revealed the presence
of glucuronide conjugates in the bile and urine of
isoquine-dosed rats. Direct glucuronidation of parent
compound (ISQ 1) was also seen, suggesting that the
hydroxyl group is no longer restricting Phase II conjugation.
</p>
<p>Scheme <xref rid="jm030796nh00004"></xref>
summarizes the main metabolites from
isoquine that were identified in this initial study. Note
that amodiaquine or its metabolites do not form glucuronides (Scheme <xref rid="jm030796nh00005"></xref>
) in sharp contrast to isoquine.
<fig id="jm030796nh00004" position="float" fig-type="scheme" orientation="portrait"><label>4</label>
<caption><p>Metabolic Scheme for Isoquine ISQ-1 (<bold>3</bold>
<bold>a</bold>
)
</p>
</caption>
<graphic xlink:href="jm030796nh00004.tif" position="float" orientation="portrait"></graphic>
</fig>
<fig id="jm030796nh00005" position="float" fig-type="scheme" orientation="portrait"><label>5</label>
<caption><p>Metabolic Scheme for Amodiaquine (<bold>2</bold>
)
</p>
</caption>
<graphic xlink:href="jm030796nh00005.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
<p>Results from this initial metabolism study have
demonstrated that interchange of the diethylamino side
chain with the hydroxyl group of AQ as in ISQ1 (<bold>3a</bold>
)
can prevent the bioactivation of this compound in vivo
and can influence the critical balance between bioactivation and detoxication. We propose that this compound
may not produce the adverse reactions seen with AQ
on the basis that no evidence of chemically reactive
metabolites could be obtained. Furthermore, interchange also provides altered routes of metabolism
whereby the hydroxyl group can facilitate “metabolic
escape”. Full details of metabolite identification, LCMS
traces, and graphs of tissue distribution have been
included as Supporting Information.
</p>
</sec>
<sec id="d7e1296"><title>Discussion</title>
<p>The hemoglobin degradation pathway in <italic toggle="yes">P. falciparum</italic>
is a specialized parasite process with a proven
history as an exploitable therapeutic target as exemplified by the 4-aminoquinolines and the endoperoxide
derivatives.<xref rid="jm030796nb00017" ref-type="bibr"></xref>
Furthermore, unlike parasite encoded
enzymes<sup>18</sup>
and transporters,<xref rid="jm030796nb00019" ref-type="bibr"></xref>
that are currently under
investigation, the parasite has difficulty in developing
resistance to these two classes of drug (compare the
speed of resistance development to chloroquine with
that for the antifolates or atovaquone).<xref rid="jm030796nb00020" ref-type="bibr"></xref>
Resistance to
chloroquine (CQ) was first reported in the late 50's, and
by the 70's there were examples of culture adapted
strains with IC<sub>50</sub>
s of 200−300 nM. Despite the continued
widespread exposure of parasite populations to CQ in
many parts of the world, resistance beyond this level is
rarely observed. Attempts to increase this level of
resistance in a laboratory setting have failed, suggesting
the parasite may have difficulty in developing resistance
strategies beyond this point. Based on this and our
understanding of 4-aminoquinoline action, the development of a new 4-aminoquinoline derivative effective
against these highly CQ resistant isolates should pose
the parasite major difficulties in terms of resistance
acquisition and would therefore have an expected useful
therapeutic lifespan in excess of many of the other drugs
currently under development.
</p>
<p>For the past 15 years we have been involved in
research aimed at understanding the mechanism(s) of
action and toxicity of and the basis of parasite resistance
to the 4-aminoquinolines.<named-content content-type="bibref-group"><xref rid="jm030796nb00021" ref-type="bibr"></xref>
,<xref rid="jm030796nb00028" ref-type="bibr">28a</xref>
-d</named-content>
Integral to our studies
of the basic biology has been the synthesis of novel
4-aminoquinoline analogues that have been used as
chemical probes to investigate structure−activity and
structure−toxicity relationships (see Chart <xref rid="jm030796nc00002"></xref>
). This
subsequently resulted in the establishment of a rational
drug design program that has now generated more than
100 chemical entities.
<fig id="jm030796nc00002" position="float" fig-type="chart" orientation="portrait"><label>2</label>
<caption><p>Approaches Leading to the Discovery of the Isoquine Class of 4-Aminoquinoline Antimalarial</p>
</caption>
<graphic xlink:href="jm030796nc00002.tif" position="float" orientation="portrait"></graphic>
</fig>
</p>
<p>Chart <xref rid="jm030796nc00002"></xref>
summarizes the different classes of 4-aminoquinoline that we have investigated in our drug development program. On the basis of the important
observation that amodiaquine retains antimalarial activity against chloroquine resistant parasites,<xref rid="jm030796nb00027" ref-type="bibr">27b</xref>
our initial studies involved the design and synthesis of fluoroamodiaquine (<bold>13a</bold>
) as a safer alternative to AQ. On the
basis of metabolism studies, <bold>13a</bold>
was chemically modified to produce a new lead compound (<bold>13b</bold>
) which expressed activity in vitro at about half the level of amodiaquine versus CQ-resistant strains, but with equivalent oral in vivo potency versus <italic toggle="yes">Plasmodium </italic>
<italic toggle="yes">berghei</italic>
.<xref rid="jm030796nb00009" ref-type="bibr"></xref>
While analogues in this series initially looked promising,
concern about cost led us to consider three other series
of synthetically more accessible analogues; the tebuquine series (<bold>14</bold>
),<xref rid="jm030796nb00011" ref-type="bibr"></xref>
the bis-Mannich series (<bold>15</bold>
),<xref rid="jm030796nb00029" ref-type="bibr"></xref>
and
the 5‘-alkyl series class of 4-aminoquinoline.<xref rid="jm030796nb00021" ref-type="bibr"></xref>
Compounds in the tebuquine and bis-Mannich series are
considerably more potent than AQ or CQ in vitro and
in vivo but have subsequently been shown to have
unacceptable toxicity profiles and extremely long half-lives.<xref rid="jm030796nb00023" ref-type="bibr"></xref>
On the basis of initial toxicological evaluation
and the fact that all three sets of amodiaquine derivative retain the 4-aminophenol “structural alert” further
investigations were not pursued. Recent studies by the
Sergheraert group have also examined analogues where
the 4‘-aminophenol alert has been modified by removal
of the 4‘ hydroxyl function. Compounds of the general
class (<bold>13c</bold>
) where shown to have excellent in vitro and
in vivo potencies.<xref rid="jm030796nb00028" ref-type="bibr">28e</xref>
</p>
<p>Our most recent studies on 4-aminoquinoline SAR
have revealed, like others,<named-content content-type="bibref-group"><xref rid="jm030796nb00030" ref-type="bibr"></xref>
,<xref rid="jm030796nb00031" ref-type="bibr"></xref>
</named-content>
that short chain two-carbon side-chain chloroquine analogues retain activity
against chloroquine resistant plasmodia. Our efforts<sup>32</sup>
were directed toward compounds less likely to undergo
metabolic<italic toggle="yes"> N</italic>
-terminal dealkylation, a process that produces <italic toggle="yes">N</italic>
-desalkyl metabolites that are considerably less
potent against chloroquine resistant strains. Some of
these 2-C analogues, e.g. <bold>16a</bold>
, display good antiparasitic
profiles.<named-content content-type="bibref-group"><xref rid="jm030796nb00030" ref-type="bibr"></xref>
−<xref rid="jm030796nb00031" specific-use="suppress-in-print" ref-type="bibr"></xref>
<xref rid="jm030796nb00032" ref-type="bibr"></xref>
</named-content>
</p>
<p>From our SAR studies, it was clear that the presence
of a 4-arylamino moiety provides analogues with
superior activity against CQ resistant strains, and it was
also apparent that the presence of an aromatic hydroxyl
function appears to be important for additional levels
of antiparasitic activity. <sup>11a</sup>
It therefore seemed reasonable that interchange of the 3‘-Mannich side chain with
the 4‘-OH function would provide a new template
capable of delivering a series of compounds chemically
incapable of forming potentially toxic quinoneimine
metabolites. Furthermore, it was proposed that analogues in this series would not only be potent against
resistant strains, but would also be as cheap to prepare
as AQ on an industrial scale.
</p>
<p>A potential drawback with any new 4-aminoquinoline
antimalarials is the possibility of cross-resistance with
chloroquine. Clearly from Table <xref rid="jm030796nt00002"></xref>
, the data presented
here demonstrates that for isoquine and several analogues, there is minimal cross-resistance with chloroquine in the highly CQ resistant K1 strain (not shown
to be statistically significant by the Mann−Whitney U
test). These observations are supported by the recent
demonstration that mutations in the pfcrt gene have a
minimal effect on the activity and accumulation of
amodiaquine compared with chloroquine. Although the
results of in vitro testing are encouraging, it is clear that
further studies will be required to include a wider panel
of chloroquine resistant isolates to fully determine the
potential utility of this new class of 4-aminoquinoline.
As shown in Table <xref rid="jm030796nt00003"></xref>
, isoquine is orally active in the
mouse model of malaria with a superior ED50 to
amodiaquine. From Table <xref rid="jm030796nt00004"></xref>
there is no correlation
between the calculated log <italic toggle="yes">P</italic>
's (ClogPs)<sup>11b</sup>
of these
derivatives and in vitro antimalarial activity against the
chloroquine sensitive HB3 strain. The same applies to
the chloroquine resistant strain, indicating that other
factors apart from lipophilicity have a role in determining the expression of in vitro antimalarial activity.
<table-wrap id="jm030796nt00004" position="float" orientation="portrait"><label>4</label>
<caption><p>Comparison of Calculated Log<italic toggle="yes">P</italic>
(ClogP) versus
Antimalarial Activity</p>
</caption>
<oasis:table colsep="2" rowsep="2"><oasis:tgroup cols="3"><oasis:colspec colnum="1" colname="1"></oasis:colspec>
<oasis:colspec colnum="2" colname="2"></oasis:colspec>
<oasis:colspec colnum="3" colname="3"></oasis:colspec>
<oasis:tbody><oasis:row><oasis:entry namest="1" nameend="1">drug<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</oasis:entry>
<oasis:entry namest="2" nameend="2">IC<sub>50 </sub>
(nM) HB3</oasis:entry>
<oasis:entry namest="3" nameend="3">ClogP<italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">chloroquine (<bold>1</bold>
)
</oasis:entry>
<oasis:entry colname="2">14.98
</oasis:entry>
<oasis:entry colname="3">5.04
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">amodiaquine (<bold>2</bold>
)
</oasis:entry>
<oasis:entry colname="2">9.60
</oasis:entry>
<oasis:entry colname="3">4.51
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">isoquine (ISQ-1) (<bold>3a</bold>
)
</oasis:entry>
<oasis:entry colname="2">12.65
</oasis:entry>
<oasis:entry colname="3">4.51
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1">isoquine diphosphate (<bold>3b</bold>
)
</oasis:entry>
<oasis:entry colname="2">9.02
</oasis:entry>
<oasis:entry colname="3">NA
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(4a)</bold>
</oasis:entry>
<oasis:entry colname="2">30.03
</oasis:entry>
<oasis:entry colname="3">4.22
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(5a)</bold>
</oasis:entry>
<oasis:entry colname="2">14.76
</oasis:entry>
<oasis:entry colname="3">3.45
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(6a)</bold>
</oasis:entry>
<oasis:entry colname="2">19.78
</oasis:entry>
<oasis:entry colname="3">5.57
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(7a)</bold>
</oasis:entry>
<oasis:entry colname="2">51.88
</oasis:entry>
<oasis:entry colname="3">6.62
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(8a)</bold>
</oasis:entry>
<oasis:entry colname="2">28.37
</oasis:entry>
<oasis:entry colname="3">4.08
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(9a)</bold>
</oasis:entry>
<oasis:entry colname="2">97.20
</oasis:entry>
<oasis:entry colname="3">3.36
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(10a)</bold>
</oasis:entry>
<oasis:entry colname="2">9.07
</oasis:entry>
<oasis:entry colname="3">4.63
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(11a)</bold>
</oasis:entry>
<oasis:entry colname="2">20.22
</oasis:entry>
<oasis:entry colname="3">3.82
</oasis:entry>
</oasis:row>
<oasis:row><oasis:entry colname="1"><bold>(12)</bold>
</oasis:entry>
<oasis:entry colname="2">16.24
</oasis:entry>
<oasis:entry colname="3">3.51</oasis:entry>
</oasis:row>
</oasis:tbody>
</oasis:tgroup>
</oasis:table>
<table-wrap-foot><p><italic toggle="yes"><sup>a</sup>
</italic>
<sup></sup>
ClogP values calculated using the Biobyte Mac log P 4
Program.</p>
</table-wrap-foot>
</table-wrap>
</p>
<p>Chloroquine and to a lesser extent AQ are the only
4-aminoquinoline antimalarials with which we have any
real clinical experience. CQ is considered a safe drug
when used as recommended, although cardiovascular
and CNS toxicities are seen in overdose and prolonged
treatment is associated with retinopathy. However, AQ
has been shown to carry an unacceptable risk of
agranulocytosis and hepatitis when used for prophylaxis, this has resulted in deaths.<named-content content-type="bibref-group"><xref rid="jm030796nb00003" ref-type="bibr"></xref>
,<xref rid="jm030796nb00004" ref-type="bibr"></xref>
</named-content>
The toxicological
concerns are that as AQ is used more extensively,
possibly as a component of an artemisinin combination,
the incidence of these adverse drug reactions will
increase as pediatric African populations are exposed
to the drug on multiple occasions per year.
</p>
<p>There are two chemical features of AQ that are
considered to be relevant to its toxicity. First, because
it is a lipophilic weak base, it is lysosomotropic and is
therefore readily taken up by specific white cell populations. Second, as described earlier, the side-chain contains a 4-aminophenol group. This is a substructure now
widely recognized as a structural alert for toxicity by
medicinal chemists, because of metabolic oxidation to
quinonimines.<named-content content-type="bibref-group"><xref rid="jm030796nb00006" ref-type="bibr"></xref>
,<xref rid="jm030796nb00008" ref-type="bibr"></xref>
</named-content>
For example, as described earlier,
paracetamol undergoes oxidation in the liver by cytochrome P450 enzymes to <italic toggle="yes">N</italic>
-acetyl <italic toggle="yes">p</italic>
-benzoquinonimine,
the cause of massive irreversible hepatic necrosis when
the drug is taken in overdose. We have shown that AQ
readily undergoes oxidation to a quinoneimine.<xref rid="jm030796nb00005" ref-type="bibr"></xref>
Oxidation is more likely to occur with AQ than paracetamol
because of its lower oxidation potential.<xref rid="jm030796nb00009" ref-type="bibr"></xref>
Extensive
metabolic studies, in a variety of model systems, have
shown that the oxidation of AQ can be catalyzed by
myeoloperoxidase, hypochlorous acid (both released by
activated white cells), and cytochrome P450 enzymes.
The quinoneimine has been trapped and characterized
as a glutathione conjugate which provides a biomarker
for the in vivo bioactivation of the drug. AQ undergoes
extensive bioactivation in the mouse and the rat.<named-content content-type="bibref-group"><xref rid="jm030796nb00005" ref-type="bibr"></xref>
−<xref rid="jm030796nb00006" specific-use="suppress-in-print" ref-type="bibr"></xref>
<xref rid="jm030796nb00007" ref-type="bibr"></xref>
</named-content>
One
reason for the extensive bioactivation of AQ is that the
phenolic group is refractory to <italic toggle="yes">O</italic>
-glucuronidation, the
normal pathway of biochemical detoxication that one
would anticipate for such a molecule. We attribute this
to a combination of the p<italic toggle="yes">K</italic>
<sub>a</sub>
of the group and strong
internal hydrogen bonding with the <italic toggle="yes">O</italic>
-diethylamino
group. Removal of the Mannich side-chain permits
phase II detoxication reactions. AQ also undergoes
bioactivation to a quinoneimine in human neutrophils,
and a similar metabolic process was observed for pyronaridine and amopyroquine.<xref rid="jm030796nb00024" ref-type="bibr"></xref>
</p>
<p>What are the toxicological consequences of bioactivation? It should first be stated that the formation of
glutathione conjugates of AQ does represent detoxication. Nevertheless, at doses of AQ that are not acutely
toxic, covalent modification of hepatic proteins has been
demonstrated in the rat after only a single dose of the
drug. Furthermore we have demonstrated that AQ is
weakly immunogenic and AQ quinoneimine is extremely
immunogenic in an animal model.<xref rid="jm030796nb00005" ref-type="bibr"></xref>
More importantly,
we have demonstrated the presence of specific antidrug
(metabolite) antibodies in a cohort of patients with
serious adverse drug reactions to AQ.<xref rid="jm030796nb00007" ref-type="bibr"></xref>
Thus the mechanism is consistent with that of other drugs such as
penicillin and aminopyrine which cause type II hypersensitivity reactions in man.<xref rid="jm030796nb00015" ref-type="bibr"></xref>
There are no animal
models currently available to test for such reactions in
preclinical screens. Nevertheless, there are now clearly
defined structural alerts in minor drug metabolites for
such immune-mediated toxicities.
</p>
<p>The strategy we have adopted is one in which we have
designed the chemical alert out of the drug structure
while retaining antimalarial activity. A similar strategy
has been successfully employed in the redesign of
general anesthetics and β-blockers currently in clinical
use. This modification has resulted in a marked shift
in the pattern of metabolism in the rat, which carries
pharmacological benefits; thus in the rat model, it was
observed that for isoquine there is a complete absence
of glutathione conjugates in the bile. This clearly
illustrates the lack of bioactivation of the 4-amino
arylalkyl side-chain. Cleavage of the side-chain by P450
enzymes is the primary Phase 1 biotransformation. This
biotransformation reduces steric hindrance around the
phenolic hydroxyl group and enables efficient Phase II
glucuronidation. The <italic toggle="yes">O</italic>
-glucuronide is rapidly excreted
in the bile and does not accumulate in tissues. This
metabolic pathway sharply contrasts with that of AQ
where the major dealkylated metabolite, desethyl AQ,
accumulates in the liver.
</p>
<p>One of the primary biotransformations of ISQ1 involves cleavage of the dialkylamino side-chain. We (and
others) have shown that this side chain is essential for
pharmacological activity. Therefore, we can propose that
the in vivo pharmacological response of isoquine will be
related to plasma/tissue concentrations of parent drug
or the <italic toggle="yes">N</italic>
-desethyl metabolite (<bold>12a</bold>
), as is the case for
amodiaquine. This may be important in terms of cross-resistance patterns with CQ since the desethyl metabolite of AQ rather than parent drug is the main circulating metabolite in man<sup>16b</sup>
and this metabolite demonstrates more cross resistance to CQ than the parent
drug which may have clinical consequences.<xref rid="jm030796nb00016" ref-type="bibr"></xref>
This may
be a potential concern with isoquine, and a much more
detailed study on the identity and antimalarial activity
of main plasma metabolites will have to be conducted
in future work.<xref rid="jm030796nb00016" ref-type="bibr">16d</xref>
</p>
<p>As with all new entities, it is true that until we
have clinical experience, toxicity cannot be ruled out.
However, we can be certain that the chemical rearrangement in isoquine and its analogues precludes the
formation of a reactive quinonimine. Furthermore,
initial studies described here in rodents indicate that
isoquine is eliminated at least as quickly as AQ;
therefore, we can anticipate that toxicity due to accumulation will not be an issue. The 4-aminoquinolines
as a drug class give no other obvious cause for concern based on clinical experience. As outlined above, the
type of toxicity that has been associated with AQ is a
type II idiosyncratic response characterized, as described above, as nonpredictable. Therefore, there will
always remain a real concern that AQ can illicit this
form of toxicity when used clinically. The more widespread use of AQ both as monotherapy and in combination, the exposure to multiple doses in high transmission
areas, and the use of the drug in HIV +ve individuals
suggest it may be unwise to give a safety recommendation based on the earlier retrospective analysis of
prophylactic subjects. It is clear that the presence of this
metabolic alert in a new drug entity would terminate
its further development by the pharmaceutical industry
today.
</p>
<p>In summary, our initial studies suggest that the
isomeric series of amodiaquine analogues presented in
this publication are worthy of further investigation as
potential, safer alternatives to amodiaquine. In particular, isoquine ISQ1 (<bold>3a</bold>
) appears to have many advantages over the clinically used derivatives in this class.
As such, isoquine<sup>36</sup>
and other members of this isomeric
class are currently the subject of preclinical evaluation
in a partnership between the Malaria for Medicines
Venture (MMV) and Glaxo Smithkline Pharmaceuticals.
</p>
</sec>
<sec id="d7e1665"><title>Experimental Section</title>
<p><bold>Chemistry.</bold>
Unless otherwise noted, all solvents and reagents were obtained from commercial suppliers and used
without further purification. The 3-hydroxyacetoamidophenol
and all of the corresponding amines used in the experiments
were purchased from Aldrich Chemical Co. Analytical thin-layer chromatography (TLC) was performed on aluminum
sheets precoated with silica gel obtained from Merck. Visualization was accomplished by UV light (254 nm). Column
chromatography was carried out on Merck 938S silica gel.
Infrared (IR) spectra were recorded in the range 4000−600
cm<sup>-1</sup>
using a Perkin-Elmer 298 infrared spectrometer. Solid
samples were run as Nujol mulls and liquids neat on sodium
chloride disks, as indicated in text. Proton NMR spectra were
recorded using Brucker (400, 250, and 200 MHz) NMR
spectrometers as clarified in text. Spectra were referenced to
the residual solvent peak and chemical shifts expressed in ppm
from the internal reference peak. Significant <sup>1</sup>
HNMR data are
written in order: number of protons, multiplicity (b, broad; s,
singlet; d, doublet; t, triplet; q, quartet; m, multiple; bs, broad-singlet, bm, broad-multiplet), coupling constants in hertz,
assignment. Mass spectra were recorded at 70 eV using a
VG7070E and/or micromass LCT mass spectrometers. The
molecular ion M<sup>+</sup>
, with intensities in parentheses, is given
followed by peaks corresponding to major fragment losses.
Melting points were performed using a Gallemkamp melting
point apparatus and are reported uncorrected. Elemental
analyses were performed in the microanalysis laboratory in
the Department of Chemistry, University of Liverpool.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(4-Diethylaminomethyl-3-hydroxyphenyl)acetamide (3). </bold>
3-Hydroxyacetanilide (5 g, 33.1 mmol) was added
to 100 mL round-bottom flask followed by ethanol (23.6 mL).
One equivalent of diethylamine (3.42 mL, 33.1 mmol) and
aqueous formaldehyde (2.46 mL) was added and the solution
was allowed to heat under reflux for 24 h. After this reflux
period, the solvent was removed under reduced pressure and
the crude material was purified by silica gel flash column
chromatography using 20−80% MeOH/dichloromethane as
eluent. This gave the desired product as a pale brown oily
residue (5.31 g, 69%); <sup>1</sup>
H NMR (250 MHz, CDCl<sub>3</sub>
) δ 7.15 (bs,
1H, O<italic toggle="yes">H</italic>
), 7.05 (dd, 1H, <italic toggle="yes">J</italic>
= 8.2, 1.92 Hz, Ar-<italic toggle="yes">H</italic>
), 6.88 (d, 1H, <italic toggle="yes">J</italic>
= 8.2 Hz, Ar-<italic toggle="yes">H</italic>
), 6.80 (d, 1H, <italic toggle="yes">J</italic>
= 1.92 Hz, Ar-<italic toggle="yes">H</italic>
), 3.71 (s, 2H,
C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.59 (q, 4H, <italic toggle="yes">J</italic>
= 7.20 Hz, NC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>3</sub>
), 2.13 (s, 3H,
COC<italic toggle="yes">H</italic>
<sub>3</sub>
), 1.07 (t, 6H, <italic toggle="yes">J</italic>
= 7.20 Hz, NCH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100
MHz, CDCl<sub>3</sub>
) δ 172.03, 160.17, 140.76, 130.33, 119.83, 112.40,
109.35, 72.04, 57.48, 47.92, 24.28, 11.94; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
237 [M
+ H]<sup>+</sup>
(100), 164 (28), 122 (12), 74 (61), 58 (32); IR (neat):
3500−2800 (broad-OH band), 1668, 1614, 1538, 1454, 1386,
1273, 1194, 1166, 1114, 1032, 863, 773 and 736 cm<sup>-1</sup>
; HRMS
<italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>13</sub>
H<sub>21</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 237.16029 found, 237.16042.
Anal. (C<sub>13</sub>
H<sub>20</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-[4-(</bold>
<bold><italic toggle="yes">tert</italic>
</bold>
<bold>-Butylaminomethyl)-3-hydroxyphenyl]acetamide (4). </bold>
Compound <bold>4</bold>
was prepared in a manner similar to
Mannich base <bold>3</bold>
to give the product as a white solid (70%
yield): <sup>1</sup>
H NMR (200 MHz, CDCl<sub>3</sub>
) δ 8.15 (s, 1H, Ar-<italic toggle="yes">H</italic>
), 6.95
(d, 1H, <italic toggle="yes">J</italic>
= 8.30 Hz, Ar-<italic toggle="yes">H</italic>
), 6.51 (d, 1H, <italic toggle="yes">J</italic>
= 8.30 Hz, Ar-<italic toggle="yes">H</italic>
),
3.72 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.17 (s, 3H), 1.18 (s, 9H, <italic toggle="yes">t</italic>
-Bu). Anal.
(C<sub>13</sub>
H<sub>20</sub>
N<sub>2</sub>
O<sub>2</sub>
) C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(4-Dimethylaminomethyl-3-hydroxyphenyl)acetamide (5).</bold>
Compound <bold>5</bold>
was prepared in a manner similar to
Mannich base <bold>3</bold>
to give the product as an off-white solid
(74%): mp = 135−136 °C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
<italic toggle="yes">)</italic>
δ 7.06
(d, 1H, <italic toggle="yes">J</italic>
= 1.80 Hz, Ar-<italic toggle="yes">H</italic>
), 6.95 (d, 1H, <italic toggle="yes">J</italic>
= 8.13 Hz, Ar-<italic toggle="yes">H</italic>
),
6.91 (dd, 1H, <italic toggle="yes">J</italic>
= 8.13, 1.80 Hz, Ar-<italic toggle="yes">H</italic>
), 3.58 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.30
(s, 6H, NC<italic toggle="yes">H</italic>
<sub>3</sub>
), 2.08 (s, 3H, COC<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100 MHz,
CDCl<sub>3</sub>
) δ 168.05, 138.43, 128.66, 110.58, 107.47, 62.47, 53.41,
50.88, 44.43, 24.66; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
209 [M + H]<sup>+</sup>
(100), 164 (10),
122 (7), 58 (2); IR (Nujol mull<italic toggle="yes">)</italic>
: 3270, 1699, 1614, 1549, 1304,
1271, 1196, 1123, 1015, 975, 870, 824, 802, 763, and 727 cm<sup>-1</sup>
;
HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>11</sub>
H<sub>17</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 209.12901; found,
209.12938. Anal. (C<sub>11</sub>
H<sub>16</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(4-Dipropylaminomethyl-3-hydroxyphenyl)acetamide (6).</bold>
Compound <bold>6</bold>
was prepared in a manner similar to
Mannich base <bold>3</bold>
to provide the product as a pale brown foamy
residue (63%). <sup>1</sup>
H NMR (200 MHz, CDCl<sub>3</sub>
) δ 7.04 (dd, 1H, <italic toggle="yes">J</italic>
=
7.97 Hz, 1.92, Ar-<italic toggle="yes">H</italic>
), 6.86 (d, 1H, <italic toggle="yes">J</italic>
= 7.97 Hz, Ar-<italic toggle="yes">H</italic>
), 6.79 (d,
1H, <italic toggle="yes">J</italic>
= 1.92 Hz, Ar-<italic toggle="yes">H</italic>
), 6.58 (s, 1H, O<italic toggle="yes">H</italic>
), 3.68 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
),
2.43 (t, 4H, <italic toggle="yes">J</italic>
= 7.68 Hz, NC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>2</sub>
CH<sub>3</sub>
), 2.12 (s, 3H, COC<italic toggle="yes">H</italic>
<sub>3</sub>
),
1.50 (m, 4H, NCH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>3</sub>
), 0.85 (t, 6H, <italic toggle="yes">J</italic>
= 7.42 Hz, NCH<sub>2</sub>
CH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
) δ 170.96, 158.71, 140.25,
131.116, 119.692, 111.97, 108.77, 56.53, 49.66, 23.86, 20.60,
12.10; IR (neat) 3316, 2963, 2779, 1739, 1694, 1668, 1614,
1538, 1466, 1373, 1272, 1167, 1115, 1082, 1059, 978, 863 and
757 cm<sup>-1</sup>
; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
265 [M + H]<sup>+</sup>
(100), 164 (13), 102 (98)
72 (26); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>15</sub>
H<sub>25</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 265.19159,
found 265.19116. Anal. (C<sub>15</sub>
H<sub>24</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(4-Dibutylaminomethyl-3-hydroxyphenyl)acetamide (7).</bold>
Compound <bold>7</bold>
was prepared in a manner similar to
Mannich base <bold>3</bold>
to provide the product as a pale brown
foamy residue (52%); <sup>1</sup>
H NMR (200 MHz, CDCl<sub>3</sub>
) δ 7.33 (s,
1H, O<italic toggle="yes">H</italic>
), 7.03 (d, 1H, <italic toggle="yes">J</italic>
= 7.90 Hz, Ar-<italic toggle="yes">H</italic>
), 6.85 (d, 1H, <italic toggle="yes">J</italic>
=
7.90 Hz, Ar-<italic toggle="yes">H</italic>
), 6.78 (d, 1H, Ar-<italic toggle="yes">H</italic>
), 3.67 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.45 (t,
4H, <italic toggle="yes">J</italic>
= 7.12 Hz, NC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>2</sub>
CH<sub>2</sub>
CH<sub>3</sub>
), 2.10 (m, 4H, NCH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>2</sub>
CH<sub>3</sub>
), 1.47 (m, 4H, NCH<sub>2</sub>
CH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>3</sub>
), 0.86 (t, 6H, <italic toggle="yes">J</italic>
=
7.14 Hz, NCH<sub>2</sub>
CH<sub>2</sub>
CH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
; <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
) δ
170.85, 159.89, 140.71, 130.20, 119.98, 112.35, 109.15, 54.72,
50.08, 30.51, 21.99, 14.69; IR (Nujol mull): 3200, 1714, 1696,
1657, 1614, 1578, 1538, 1330, 1258, 1200, 1179, 1018, 980, 870,
and 760 cm<sup>-1</sup>
); MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
293 [M + H]<sup>+</sup>
(95), 130 (100), 86
(25); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>17</sub>
H<sub>29</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 293.12801,
found, 293.12837. Anal. (C<sub>17</sub>
H<sub>28</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(3-Hydroxy-4-pyrrolidin-1-ylmethylphenyl)acetamide (8).</bold>
Compound <bold>8</bold>
was prepared in a manner similar to
Mannich base <bold>3</bold>
to provide the product as a brown oily residue (80%). <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
) δ 7.10 (bs, 1H, O<italic toggle="yes">H</italic>
),
7.04 (dd, 1H, <italic toggle="yes">J</italic>
= 7.92, 2.00 Hz, Ar-<italic toggle="yes">H</italic>
), 6.91 (d, 1H, <italic toggle="yes">J</italic>
= 7.92
Hz, Ar-<italic toggle="yes">H</italic>
), 6.84 (d, 1H, <italic toggle="yes">J</italic>
= 2.00 Hz, Ar-<italic toggle="yes">H</italic>
), 3.78 (s, 2H,-C<italic toggle="yes">H</italic>
<sub>2</sub>
),
2.62 (bs, 4H, pyrrolidinyl-H), 2.15 (s, 3H, COC<italic toggle="yes">H</italic>
<sub>3</sub>
), 1.84 (bm,
4H, pyrrolidinyl-H); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
) δ 168.49,
158.94, 138.60, 129.11, 118.18, 110.96, 107.88, 62.01, 54.20,
24.36, 23.01, 23.00; IR (Nujol mull): 3250, 1668,1606, 1167,
1116, 1013, 863, and 722 cm<sup>-1</sup>
; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
235 [M + H]<sup>+</sup>
(94),
152 (18), 72 (100), 70 (19); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>13</sub>
H<sub>19</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 235.30200, found 235.30232. Anal. (C<sub>13</sub>
H<sub>18</sub>
N<sub>2</sub>
O<sub>2)</sub>
C,
H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(3-Hydroxy-4-morpholin-4-ylmethylphenyl)acetamide (9).</bold>
Compound <bold>9</bold>
was prepared in a manner similar to
Mannich base <bold>3</bold>
to provide the product as a white solid (72%):
mp 150 °C; <sup>1</sup>
H NMR (200 MHz, CDCl<sub>3</sub>
) δ 7.25 (bs, 1H, O<italic toggle="yes">H</italic>
),
6.99 (dd, 1H, <italic toggle="yes">J</italic>
= 8.24, 1.92 Hz, Ar-<italic toggle="yes">H</italic>
), 6.87 (d, 1H, <italic toggle="yes">J</italic>
= 8.24
Hz, Ar-<italic toggle="yes">H</italic>
), 6.82 (d, 1H, <italic toggle="yes">J</italic>
= 1.92 Hz, Ar-<italic toggle="yes">H</italic>
), 3.71 (bt, 4H, <italic toggle="yes">J</italic>
=
4.66 Hz, morpholinyl-H) 3.62 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.51 (bs, 4H,
morpholinyl-H), 2.11 (s, 3H, COC<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100 MHz,
CDCl<sub>3</sub>
): δ 168.28, 157.99, 138.77, 129.17, 116.77, 110.99,
107.66, 66.80, 61.45, 52.91; IR (Nujol mull): 3334, 1692, 1654,
1627, 1604, 1534, 1512, 1307, 1278, 1245, 1167, 1109, 1067,
1004, 981, 863, 847, and 716 cm<sup>-1</sup>
; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
250 [M + H]<sup>+</sup>
(68), 164 (91), 122 (100), 86 (95); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for
C<sub>13</sub>
H<sub>19</sub>
N<sub>2</sub>
O<sub>3</sub>
[M<sup>+</sup>
+ 1] 250.13174, found 250.13208. Anal.
(C<sub>13</sub>
H<sub>18</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(3-Hydroxy-4-piperidin-1-ylmethylphenyl)acetamide (10).</bold>
Compound <bold>10</bold>
was prepared in a manner similar
to Mannich base <bold>3</bold>
to give the product as a white solid (89%):
mp 172−173 °C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
) δ 7.09 (bs, 1H,
O<italic toggle="yes">H</italic>
), 7.03 (dd, 1H, <italic toggle="yes">J</italic>
= 8.11, 1.90 Hz, Ar-<italic toggle="yes">H</italic>
), 6.89 (d, 1H, <italic toggle="yes">J</italic>
=
8.11 Hz, Ar-<italic toggle="yes">H</italic>
), 6.85 (d, 1H, <italic toggle="yes">J</italic>
= 1.90 Hz, Ar-<italic toggle="yes">H</italic>
), 3.63 (s, 2H,
C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.49 (bs, 4H, piperidinyl-H), 2.14 (s, 3H, COC<italic toggle="yes">H</italic>
<sub>3</sub>
), 1.62
(bm, 4H, piperidinyl-H), 1.49 (bs, 2H, piperidinyl-H); <sup>13</sup>
C NMR
(100 MHz, CDCl<sub>3</sub>
); δ 168.50, 158.95, 138.66, 129.12, 118.18,
110.18, 110.97, 107.88, 62.09, 54.21, 26.20, 24.96, 24.96, 24.37;
IR (Nujol mull): 3307, 1669, 1609, 1325, 1305, 1296, 1191,
1102, 1037, 980, 900, 861 and 815 cm<sup>-1</sup>
; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
249 [M
+ H]<sup>+</sup>
(100), 166 (19), 86 (41), 84 (9); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for
C<sub>14</sub>
H<sub>21</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 249.16029 found 249.16061. Anal.
(C<sub>14</sub>
H<sub>20</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-[3-Hydroxy-4-(isopropylaminomethyl)phenyl]-acetamide (11).</bold>
Compound (<bold>11</bold>
) was prepared in a manner
similar to Mannich base <bold>3</bold>
to give the product as a pale brown
residue (51%); <sup>1</sup>
H NMR (250 MHz, CDCl<sub>3</sub>
) δ 7.15 (bs, 1H, O<italic toggle="yes">H</italic>
),
7.05 (dd, 1H, <italic toggle="yes">J</italic>
= 8.08 Hz, 2.05, Ar-<italic toggle="yes">H</italic>
), 6.87 (d, 1H, <italic toggle="yes">J</italic>
= 8.08
Hz, Ar-<italic toggle="yes">H</italic>
), 6.80 (d, 1H, <italic toggle="yes">J</italic>
= 2.05 Hz, Ar-<italic toggle="yes">H</italic>
), 3.91 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
),
2.24 (m, 1H, isopropyl-H), 2.11 (s, 3H, COC<italic toggle="yes">H</italic>
<sub>3</sub>
), 1.11 (d, 6H
isopropyl); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
) δ 169.79, 151.99,
139.95, 121.18, 119.75, 112.93, 110.58, 49.79, 48.28, 22.52,
16.12; IR (neat): 2982, 1687, 1682, 1614, 1539, 1427, 1276,
1203, 1135, 1026, 981, 964, 834, 799, 720 and 660 cm<sup>-1</sup>
; MS
(CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
223 [M + H]<sup>+</sup>
(100), 164 (20), 60 (90); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd
for C<sub>12</sub>
H<sub>19</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 223.14465 found 223.14532. Anal.
(C<sub>12</sub>
H<sub>18</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold><italic toggle="yes">N</italic>
</bold>
<bold>-(4-Ethylaminomethyl-3-hydroxyphenyl)acetamide
(12).</bold>
Brown oily residue (55%); <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
) δ
7.27 (d, 1H, <italic toggle="yes">J</italic>
= 1.89 Hz, Ar-<italic toggle="yes">H</italic>
), 7.11 (dd, 1H, <italic toggle="yes">J</italic>
= 8.18 Hz,
Ar-<italic toggle="yes">H</italic>
), 6.90 (dd, 1H, <italic toggle="yes">J</italic>
= 8.18, 1.89 Hz, Ar-<italic toggle="yes">H</italic>
), 3.99 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
),
2.89 (q, 2H, NHC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>3</sub>
), 2.07 (s, 3H, COC<italic toggle="yes">H</italic>
<sub>3</sub>
), 1.08 (t, 3H,
NHCH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
): δ 171.73, 148.89,
141.67, 131.66, 117.21, 112.07, 111.86, 108.54, 43.47, 23.91,
12.69; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
209 [M + H]<sup>+</sup>
(72), 166 (100), 152 (80);
HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>11</sub>
H<sub>17</sub>
N<sub>2</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 209.12900 found
209.12918. Anal. (C<sub>11</sub>
H<sub>16</sub>
N<sub>2</sub>
O<sub>2)</sub>
C, H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-diethylaminomethylphenol (3a).</bold>
Aqueous hydrochloric acid (20%) (25 mL) was
added to a round-bottom flask containing the amide <bold>2a</bold>
(4.47
g, 18.9 mmol) and the solution heated under reflux for 6 h.
The solvent was then removed in vacuo and the resulting
residue coevaporated with ethanol to give the corresponding
hydrochloride salt. 4,7-Dichloroquinoline (4.12 g, 20.8 mmol)
and ethanol (30 mL) were added, and the reaction was heated
under reflux for 12 h until completion of the reaction (determined by TLC). A pale yellow solid was obtained upon
removing the solvent under reduced pressure; this was subsequently purified by flash column chromatography using 20−80% MeOH/dichloromethane as eluent to yield the quinoline
hydrochloride salt as a yellow foamy solid (6.47 g, 80%). To
liberate the free base compound, this solid was dissolved in
distilled water (18 mL) and the solution basified by careful
dropwise addition of saturated sodium bicarbonate (added
until no more precipitate formed). Dichloromethane (100 mL)
was added, and the free base was extracted into the organic
layer. Subsequent drying and removal of solvent in vacuo
afforded the desired product as a pale off-white solid (3.76 g,
71%): mp 134−135 °C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
) δ 8.55 (d,
1H, <italic toggle="yes">J</italic>
= 5.24 Hz, quinoline-H), 8.02 (d, 1H, <italic toggle="yes">J</italic>
= 2.20 Hz,
quinoline-H), 7.83 (d, 1H, <italic toggle="yes">J</italic>
= 8.92 Hz, quinoline-H), 7.44 (dd,
1H, <italic toggle="yes">J</italic>
= 8.96, 2.16 Hz, quinoline-H), 7.04 (d, 1H, <italic toggle="yes">J</italic>
= 5.24 Hz,
quinoline-H), 6.98 (d, 1H, <italic toggle="yes">J</italic>
= 7.96 Hz Ar−H), 6.74 (d, 1H, <italic toggle="yes">J</italic>
= 2.08 Hz, Ar−H), 6.68 (dd, 1H, <italic toggle="yes">J</italic>
= 7.96, 2.22 Hz, Ar−H),
6.53 (bs, 1H, O<italic toggle="yes">H</italic>
), 3.79 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.65 (q, 4H, <italic toggle="yes">J</italic>
= 7.14 Hz,
NC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>3</sub>
), 1.14 (t, 6H, <italic toggle="yes">J</italic>
= 7.14 Hz, NCH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100
MHz, CDCl<sub>3</sub>
<bold><italic toggle="yes">)</italic>
</bold>
δ 160.44 152.35, 150.11, 147.84, 140.22, 135.57,
129.58, 129.41, 126.38, 121.54, 119.27, 118.53, 113.17, 110.54,
103.28, 56.99, 46.72, 11.57; IR (Nujol mull) 2930, 2858, 1668,
1612, 1575, 1529, 1459, 1424, 1378, 1327, 1277, 1192, 1178,
1159, 1115, 1079, 992, 974, 907, 873, 855, 814 and 772 cm<sup>-1</sup>
;
MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
356 [M + H]<sup>+</sup>
(100), 285 (24), 271 (92), 110 (100);
HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>20</sub>
H<sub>23</sub>
ClN<sub>3</sub>
O [M<sup>+</sup>
+ 1] 356.15292 found,
356.15169. Anal. (C<sub>20</sub>
H<sub>22</sub>
ClN<sub>3</sub>
O) C, H, N.
</p>
<p><bold>2-(</bold>
<bold><italic toggle="yes">tert</italic>
</bold>
<bold>-Butylaminomethyl)-5-(7-chloroquinolin-4-ylamino)phenol (4a). </bold>
This compound was prepared in a manner
similar to <bold>3a</bold>
to provide a pale yellow solid (69%); <sup>1</sup>
H NMR
(400 MHz, CDCl<sub>3</sub>
<bold><italic toggle="yes">)</italic>
</bold>
δ 8.52 (d, 1H, <italic toggle="yes">J</italic>
= 5.30 Hz, quinoline-H),
8.01 (d, 1H <italic toggle="yes">J</italic>
= 2.14 Hz, quinoline-H), 7.85 (d, 1H, <italic toggle="yes">J</italic>
= 8.90
Hz, quinoline-H), 7.43 (dd, 1H, <italic toggle="yes">J</italic>
= 8.90, 2.14 Hz, quinoline-H), 7.02 (d, 1H, <italic toggle="yes">J</italic>
= 5.32 Hz, quinoline-H), 6.99 (d, 1H, <italic toggle="yes">J</italic>
=
7.98 Hz, Ar−H), 6.76 (d, 1H, <italic toggle="yes">J</italic>
= 2.20 Hz, Ar−H), 6.68 (dd,
1H, <italic toggle="yes">J</italic>
= 7.96, 2.20 Hz, Ar−H), 6.63 (bs, 1H, O<italic toggle="yes">H</italic>
), 3.99 (s, 2H,
CH<sub>2</sub>
), 1.20 (s, 9H, <italic toggle="yes">t</italic>
-Bu). Anal. (C<sub>20</sub>
H<sub>22</sub>
ClN<sub>3</sub>
O) C, H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-dimethylamino-methylphenol (5a).</bold>
This compound was prepared in a
manner similar to <bold>3a</bold>
to provide a pale yellow solid (69%). mp
176.6−177.8 °C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
) δ 8.56 (d, 1H, <italic toggle="yes">J</italic>
= 5.40 Hz, quinoline-H), 8.04 (d, 1H, <italic toggle="yes">J</italic>
= 2.06 Hz, quinoline-H), 7.84 (d, 1H, <italic toggle="yes">J</italic>
= 9.06 Hz, quinoline-H), 7.45 (dd, 1H, <italic toggle="yes">J</italic>
=
9.06, 2.06 Hz quinoline-H), 7.05 (d, 1H, <italic toggle="yes">J</italic>
= 5.40 Hz, quinoline-H), 6.98 (d, 1H, <italic toggle="yes">J</italic>
= 7.95, Ar−H), 6.76 (d, 1H, <italic toggle="yes">J</italic>
= 2.22 Hz,
Ar−H), 6.69 (dd, 1H, <italic toggle="yes">J</italic>
= 7.95, 2.22 Hz, Ar−H), 6.51 (bs, 1H,
O<italic toggle="yes">H</italic>
), 3.67 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.37 (s, 6H, NC<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100 MHz,
CDCl<sub>3</sub>
) δ 159.78, 152.37, 149.50, 149.4, 146.60, 134.60, 129.59,
129.47, 126.42, 121.50, 119.04, 113.18, 110.39, 103.35, 62.86,
44.83, 31.24; IR (Nujol mull<bold><italic toggle="yes">)</italic>
</bold>
3194, 2376, 2306, 1702, 1684,
1653, 1458, 1375, and 1107 cm<sup>-1</sup>
; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
328 [M +
H]<sup>+</sup>
(76), 285 (100), 251 (20), 63 (20); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for
C<sub>18</sub>
H<sub>19</sub>
ClN<sub>3</sub>
O [M<sup>+</sup>
+ 1] 328.12164 found, 328.12123. Anal.
(C<sub>18</sub>
H<sub>18</sub>
ClN<sub>3</sub>
O) C, H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-dipropylaminomethylphenol (6a).</bold>
This compound was prepared in a manner
similar to <bold>3a</bold>
to provide a pale yellow solid (61%). mp
183−184 °C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
) δ 8.56 (d, 1H, <italic toggle="yes">J</italic>
=
5.40 Hz, quinoline-H), 8.03 (d, 1H, <italic toggle="yes">J</italic>
= 2.20 Hz, quinoline-H),
7.84 (d, 1H, <italic toggle="yes">J</italic>
= 8.90 Hz, quinoline-H), 7.45 (dd, 1H, <italic toggle="yes">J</italic>
=
8.90, 2.22 Hz, quinoline-H), 7.06 (d, 1H, <italic toggle="yes">J</italic>
= 5.41 Hz, quinoline-H), 6.98 (d, 1H, <italic toggle="yes">J</italic>
= 7.95 Hz, Ar−H), 6.74 (d, 1H, <italic toggle="yes">J</italic>
= 2.22
Hz, Ar−H), 6.69 (dd, 1H, <italic toggle="yes">J</italic>
= 7.95, 2.22 Hz, Ar−H), 6.55
(bs, 1H, O<italic toggle="yes">H</italic>
), 3.79 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.60 (t, 4H, <italic toggle="yes">J</italic>
= 7.63 Hz,
NC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>2</sub>
), 1.59 (m, 4H, NCH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>2</sub>
), 0.92 (t, 6H, <italic toggle="yes">J</italic>
= 7.31
Hz, CH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
) δ 159.87, 152.37,
150.14, 149.4, 147.76, 140.24, 135.57, 129.57, 129.46, 126.39,
121.50, 119.41, 113.13, 110.42, 103.30, 58.28, 55.83; IR (Nujol
mull) 3150, 1733, 1699, 1657,1578, 1538, 1331, 1258, 1181,
1159, 980, 855, 807 and 721 cm<sup>-1</sup>
; MS (ES+) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
384.2 [M +
H]<sup>+</sup>
(100), 283 (82), 192.6 (34); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd. for C<sub>22</sub>
H<sub>27</sub>
N<sub>3</sub>
OCl (M<sup>+</sup>
+ 1) 384.1843 found 384.1845. Anal. (C<sub>22</sub>
H<sub>26</sub>
ClN<sub>3</sub>
O)
C, H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-dibutylaminomethylphenol (7a).</bold>
This compound was prepared in a manner
similar to <bold>3a</bold>
to provide a pale brown solid (58%). mp 153 °C;
<sup>1</sup>
H NMR (200 MHz, CDCl<sub>3</sub>
) δ 8.53 (d, 1H, <italic toggle="yes">J</italic>
= 5.22 Hz,
quinoline-H), 8.00 (d, 1H, <italic toggle="yes">J</italic>
= 2.20 Hz, quinoline-H), 7.83 (d,
1H, <italic toggle="yes">J</italic>
= 9.08 Hz, quinoline-H), 7.42 (dd, 1H, <italic toggle="yes">J</italic>
= 9.0, 2.22 Hz,
quinoline-H), 7.03 (d, 1H, <italic toggle="yes">J</italic>
= 5.50 Hz, quinoline-H), 6.96 (d,
1H, <italic toggle="yes">J</italic>
= 7.98 Hz, Ar−H), 6.72 (d, 1H, <italic toggle="yes">J</italic>
= 2.00 Hz, Ar−H),
6.67 (dd, 1H, <italic toggle="yes">J</italic>
= 7.98, 2.00 Hz Ar−H), 6.54 (bs, 1H, O<italic toggle="yes">H</italic>
), 3.75
(s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.52 (t, 4H, <italic toggle="yes">J</italic>
= 7.14 Hz, NC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>2</sub>
), 1.50 (m,
4H, CH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>2</sub>
), 1.30 (m, 4H, CH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>3</sub>
) 0.90 (t, 6H, <italic toggle="yes">J</italic>
=
7.31 Hz, CH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
) δ 159.55,
152.03, 149.85, 149.79, 147.44, 135.21, 129.24, 129.11, 127.93,
126.02, 121.16, 118.19, 112.82, 110.11, 102.94, 57.85, 53.23,
28.45, 20.62, 13.96; IR (Nujol mull) 3190, 2354, 1739, 1733,
1714, 1699, 1696, 1657, 1654, 1614, 1578, 1538, 1330, 1258,
1200, 1179, 1159, 1118, 980, 909, 870, 856, 818 and 760 cm<sup>-1</sup>
;
MS (ES+) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
412.2 [M + H]<sup>+</sup>
(100), 283 (92), 206 (65); HRMS
<italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>24</sub>
H<sub>31</sub>
N<sub>3</sub>
OCl [M<sup>+</sup>
+ 1] 412.2156 found 412.2150.
Anal. (C<sub>24</sub>
H<sub>30</sub>
ClN<sub>3</sub>
O) C, H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-pyrrolidin-1-ylmethylphenol (8a).</bold>
This compound was prepared in a manner
similar to <bold>3a</bold>
to provide an off-white solid (80%): mp 163.1
°C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
<bold><italic toggle="yes">)</italic>
</bold>
δ 8.55 (d, 1H, <italic toggle="yes">J</italic>
= 5.41 Hz,
quinoline-H), 8.02 (d, 1H, <italic toggle="yes">J</italic>
= 2.07 Hz, quinoline-H), 7.84 (d,
1H, <italic toggle="yes">J</italic>
= 9.06 Hz, quinoline-H), 7.44 (dd, 1H, <italic toggle="yes">J</italic>
= 9.06, 2.07
Hz, quinoline-H), 7.03 (d, 1H, <italic toggle="yes">J</italic>
= 5.41 Hz, quinoline-H), 6.99
(d, 1H, <italic toggle="yes">J</italic>
= 7.95 Hz, Ar−H), 6.75 (d, 1H, <italic toggle="yes">J</italic>
= 2.06 Hz, Ar−H),
6.68 (dd, 1H, <italic toggle="yes">J</italic>
= 7.95, 2.07 Hz, Ar−H), 6.59 (bs, 1H, O<italic toggle="yes">H</italic>
),
3.85 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.65 (bm, 4H, pyrrolidinyl-H), 1.90 (bm,
4H, pyrrolidinyl-H); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
<bold><italic toggle="yes">) </italic>
</bold>
δ 159.41,
151.98, 149.75, 147.54, 139.92, 135.24, 129.04, 128.77, 126.03,
121.24, 119.31, 118.19, 112.84, 110.07, 102.92, 58.50, 53.55,
23.72; IR (Nujol mull) 3175, 1667, 1652, 1615, 1576, 1536,
1512, 1457, 1427, 1376 cm<sup>-1</sup>
; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
354 [M + H]<sup>+</sup>
(65),
285 (100), 271 (35), 72 (93); HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>20</sub>
H<sub>21</sub>
ClN<sub>3</sub>
O
[M<sup>+</sup>
+ 1] 354.13730 found 354.13713 Anal. (C<sub>20</sub>
H<sub>20</sub>
ClN<sub>3</sub>
O) C,
H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-morpholin-4-ylmethylphenol (9a).</bold>
This compound was prepared in a manner
similar to <bold>3a</bold>
to provide the desired product an off-white solid
(60%): mp 185−186°C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
) δ 8.56 (d,
1H, <italic toggle="yes">J</italic>
= 5.25 Hz, quinoline-H), 8.04 (d, 1H, <italic toggle="yes">J</italic>
= 2.06 Hz,
quinoline-H), 7.84 (d, 1H, <italic toggle="yes">J</italic>
= 8.91 Hz, quinoline-H), 7.45 (dd,
1H, <italic toggle="yes">J</italic>
= 8.91, 2.06 Hz, quinoline-H), 7.04 (d, 1H, <italic toggle="yes">J</italic>
= 5.25 Hz,
quinoline-H), 7.01 (d, 1H, <italic toggle="yes">J</italic>
= 7.95 Hz, Ar−H), 6.77 (d, 1H, <italic toggle="yes">J</italic>
= 2.22 Hz, Ar−H), 6.72 (dd, 1H, <italic toggle="yes">J</italic>
= 7.95, 2.22 Hz, Ar−H),
6.52 (bs, 1H, O<italic toggle="yes">H</italic>
), 3.78 (bm, 4H, morpholinyl-H), 3.73 (s, 2H
C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.60 (bm, 4H, morpholinyl-H); <sup>13</sup>
C NMR (100 MHz,
CDCl<sub>3</sub>
) δ 159.19, 152.33, 150.13, 147.63, 140.80, 135.66, 130.16,
129.46, 126.50, 121.51, 117.64, 113.46, 110.34, 103.44, 102.23,
67.16, 61.87, 53.32; IR (Nujol mull) 3200, 1699, 1654, 1575,
1533, 1346, 1335, 1249, 1118, 862 and 811 cm<sup>-1</sup>
; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
370 [M + H]<sup>+</sup>
(100), 285 (71), 251 (30), 208 (34) 164 (26); HRMS
<italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>20</sub>
H<sub>21</sub>
ClN<sub>3</sub>
O<sub>2</sub>
[M<sup>+</sup>
+ 1] 370.13223 found 370.13276.
Anal. (C<sub>20</sub>
H<sub>20</sub>
ClN<sub>3</sub>
O<sub>2</sub>
) C, H,N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-piperidin-1-ylmethylphenol (10a).</bold>
This compound was prepared in a manner
similar to <bold>3a</bold>
to provide the desired product as an off-white
solid (71%): mp 182.6; <sup>1</sup>
H NMR (200 MHz, CDCl<sub>3</sub>
) δ 8.53 (d,
1H, <italic toggle="yes">J</italic>
= 5.22 Hz, quinoline-H), 8.00 (d, 1H, <italic toggle="yes">J</italic>
= 1.92 Hz,
quinoline-H), 7.83 (d, 1H, <italic toggle="yes">J</italic>
= 9.06 Hz, quinoline-H), 7.42 (dd,
1H, <italic toggle="yes">J</italic>
= 9.06, 1.92 Hz, quinoline-H), 7.03 (d,1H, <italic toggle="yes">J</italic>
= 5.22 Hz,
quinoline-H), 6.97 (d, 1H, <italic toggle="yes">J</italic>
= 7.98 Hz, Ar−H), 6.73 (d, 1H, <italic toggle="yes">J</italic>
= 2.06 Hz, Ar−H), 6.67 (dd, 1H, <italic toggle="yes">J</italic>
= 7.98, 2.06 Hz, Ar−H),
6.58 (bs, 1H, O<italic toggle="yes">H</italic>
), 3.67 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.51 (bm, 4H, piperidinyl-H), 1.64 (bm, 6H, pyrrolidinyl-H); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
)159.81, 152.31, 150.06, 147.85, 140.26, 135.61, 129.74, 129.39,
126.40, 121.53, 118.78, 118.52, 113.21, 110.48, 103.29, 62.14,
54.28, 26.22, 24.35; MS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
368 [M + H]<sup>+</sup>
(70), 285 (100),
271 (37), 86 (93); IR (Nujol mull) 3200, 1614, 1575, 1455, 1377,
1249, 1198 and 822 cm<sup>-1</sup>
; HRMS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>21</sub>
H<sub>23</sub>
ClN<sub>3</sub>
O
[M<sup>+</sup>
+ 1] 368.15292 found 368.15403. Anal. (C<sub>21</sub>
H<sub>22</sub>
ClN<sub>3</sub>
O) C,
H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-(isopropylamino-methyl)phenol (11a).</bold>
This compound was prepared in a
manner similar to <bold>3a</bold>
to provide the product as a pale yellow
solid (67%): mp 157.6−158.2; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
<bold><italic toggle="yes">)</italic>
</bold>
δ
8.55 (d, 1H <italic toggle="yes">J</italic>
= 5.32 Hz, quinoline-H), 8.03 (d, 1H, <italic toggle="yes">J</italic>
= 2.08
Hz, quinoline-H), 7.84 (d, 1H, <italic toggle="yes">J</italic>
= 8.90 Hz, quinoline-H),
7.49 (dd, 1H, <italic toggle="yes">J</italic>
= 8.90, 2.08 Hz, quinoline-H), 7.02 (d, 1H, <italic toggle="yes">J</italic>
=
5.30 Hz, quinoline-H), 6.99 (d, 1H, <italic toggle="yes">J</italic>
= 7.92 Hz, Ar−H), 6.75
(d, 1H, <italic toggle="yes">J</italic>
= 2.24 Hz, Ar−H), 6.69 (dd,1H, <italic toggle="yes">J</italic>
= 7.92, 2.24 Hz,
Ar−H), 6.51 (bs, 1H, O<italic toggle="yes">H</italic>
), 4.02 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.93 (septet, <italic toggle="yes">J</italic>
=
6.36 Hz, 1H, isopropyl-H), 1.19 (d, 6H, <italic toggle="yes">J</italic>
= 6.36 Hz, isopropyl-H); <sup>13</sup>
C NMR (100 MHz, CDCl<sub>3</sub>
) δ 159.79, 151.99, 149.76,
147.49, 139.95, 135.24, 129.08, 128.98, 126.04, 121.18, 119.75,
118.18, 112.93, 110.58, 102.91, 49.79, 48.28, 22.52. IR (Nujol
mull) 3280, 1600, 1576, 1429, 1333, 1280, 1179, 1159, 1118,
814 and 761 cm<sup>-1</sup>
; MS <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
342.1 [M + H]<sup>+</sup>
(100), 283 (30), 171
(76); HRMS (ES+) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>19</sub>
H<sub>21</sub>
ClN<sub>3</sub>
O [M<sup>+</sup>
+ 1]
342.1373 found 342.1377. Anal. (C<sub>19</sub>
H<sub>20</sub>
Cl N<sub>3</sub>
O) C, H, N.
</p>
<p><bold>5-(7-Chloroquinolin-4-ylamino)-2-ethylaminomethylphenol (12a).</bold>
This compound was prepared in a manner
similar to <bold>3a</bold>
to provide the product as a pale brown solid
(68%). mp 136.3−131.7 °C; <sup>1</sup>
H NMR (400 MHz, CDCl<sub>3</sub>
<bold><italic toggle="yes">)</italic>
</bold>
8.54
(d, 1H, <italic toggle="yes">J</italic>
= 5.32 Hz, quinoline-H), 8.01 (d, 1H, <italic toggle="yes">J</italic>
= 2.14 Hz,
quinoline-H), 7.85 (d, 1H, <italic toggle="yes">J</italic>
= 8.95 Hz, quinoline-H), 7.43 (dd,
1H, <italic toggle="yes">J</italic>
= 8.95, 2.14 Hz, quinoline-H), 7.02 (d, 1H, <italic toggle="yes">J</italic>
= 5.32 Hz,
quinoline-H), 6.99 (d, 1H, <italic toggle="yes">J</italic>
= 7.98 Hz, Ar−H), 6.76 (d, 1H, <italic toggle="yes">J</italic>
= 2.20 Hz, Ar−H), 6.68 (dd, 1H, <italic toggle="yes">J</italic>
= 7.96, 2.20 Hz, Ar−H),
6.63 (bs, 1H, O<italic toggle="yes">H</italic>
), 4.02 (s, 2H, C<italic toggle="yes">H</italic>
<sub>2</sub>
), 2.76 (q, 2H, <italic toggle="yes">J</italic>
= 7.17 Hz
NHC<italic toggle="yes">H</italic>
<sub>2</sub>
CH<sub>3</sub>
), 1.19 (t, 3H, <italic toggle="yes">J</italic>
= 7.17 Hz, NHCH<sub>2</sub>
C<italic toggle="yes">H</italic>
<sub>3</sub>
); <sup>13</sup>
C NMR
(100 MHz, CDCl<sub>3</sub>
) 159.70, 151.97, 149.74, 147.53, 139.99,
135.23, 129.16, 129.01, 126.01, 121.26, 119.32, 118.20, 112.93,
110.48, 102.92, 52.10, 43.08, 14.83; IR 3274, 1615, 1573, 1542,
1461, 1336, 1282, 1113, 1082, 886, 909, 818 and 764 cm<sup>-1</sup>
; MS
<italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
328 [M + H]<sup>+</sup>
(10), 285 (29), 271 (100), 207 (89) 91 (22),
58 (14); HRMS (CI) <italic toggle="yes">m</italic>
/<italic toggle="yes">z</italic>
calcd for C<sub>18</sub>
H<sub>19</sub>
ClN<sub>3</sub>
O [M<sup>+</sup>
+ 1]
328.1216 found 328.12155. Anal. (C<sub>18</sub>
H<sub>18</sub>
ClN<sub>3</sub>
O) C, H, N.
</p>
<p><bold>Biology.</bold>
<bold>In Vitro Testing Protocol.</bold>
<bold>Antimalarial Activity. </bold>
Two strains of <italic toggle="yes">P. falciparum</italic>
were used in this study:
(a) The K1 strain which is known to be CQ resistant and (b)
the HB3 strain which is sensitive to all antimalarials. Parasites were maintained in continuous culture using the method
of Jensen and Trager.<xref rid="jm030796nb00033" ref-type="bibr"></xref>
Cultures were grown in flasks containing human erythrocytes (2−5%) with parasitemia in the range
of 1% to 10% suspended in RPMI 1640 medium, supplemented
with 25 mM HEPES and 32 mM NaHCO<sub>3</sub>
, and 10% human
serum (complete medium). Cultures were gassed with a
mixture of 3% O<sub>2</sub>
, 4% CO<sub>2</sub>
, and 93% N<sub>2</sub>
. Antimalarial activity
was assessed with an adaption of the 48-h sensitivity assay of
Desjardins et al. using [<sup>3</sup>
H]-hypoxanthine incorporation as an
assessment of parasite growth.<xref rid="jm030796nb00034" ref-type="bibr"></xref>
Stock drug solutions were
prepared in 100% dimethyl sulfoxide (DMSO) and diluted to
the appropriate concentration using complete medium. Assays
were performed in sterile 96-well microtiter plates, and each
plate contained 200 μL of parasite culture (2% parasitemia,
0.5% haematocrit) with or without 10 μL drug dilutions. Each
drug was tested in triplicate and parasite growth compared
to control wells (which consituted 100% parasite growth). After
24-h incubation at 37 °C, 0.5 μCi hypoxanthine was added to
each well. Cultures were incubated for a further 24 h before
they were harvested onto filter-mats, dried for 1 h at 55 °C,
and counted using a Wallac 1450 Microbeta Trilux Liquid
scintillation and luminescence counter. IC<sub>50</sub>
values were
calculated by interpolation of the probit transformation of the
log dose−response curve.
</p>
<p><bold>In Vivo Testing Protocol</bold>
<bold><italic toggle="yes">.</italic>
</bold>
<xref rid="jm030796nb00035" ref-type="bibr"></xref>
Male, random Swiss albino
mice weighing 18−22 g were inoculated intraperitoneally with
10<sup>7</sup>
parasitized erythrocytes with <italic toggle="yes">P. yoelii</italic>
NS strain. Animals
were then dosed daily via two routes (intraparential or oral)
for four consecutative days beginning on the day of infection.
Compounds were dissolved or suspended in the vechile solution
consisting of methanol, phosphate-buffered saline, and DMSO
(2:5:3 v/v). The parasitemia was determined on the day
following the last treatment and the ED<sub>50</sub>
(50% suppression
of parasites when compared to vehicle only treated controls)
calculated from a plot of log dose against parasitemia.
</p>
<p><bold>Metabolism Studies. Materials.</bold>
Opti-solv tissue solubilizer was a product of Wallac (Loughborough U.K). Ultima-gold liquid scintillation fluid was purchased from Packard
bioscience. Glacial acetic acid was a Merck product. [<sup>3</sup>
H]AQ
and [<sup>3</sup>
H]ISQ were synthesized by the University of Liverpool.
Heparin was a product of CP pharmaceuticals (Wrexham UK).
All other chemicals used were purchased from Sigma (Poole,
U.K.)
</p>
<p><bold>Statistics.</bold>
All values are given as the mean ± SEM. All
statistical analyses were carried out using a Mann−Whitney
test, and the differences were deemed significant at <italic toggle="yes">p</italic>
< 0.05
</p>
<p><bold>Investigation of Biliary and Urinary Excretion of [</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H]
AQ and [</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H] ISQ after </bold>
<bold>Administration to Male Wistar
Rats.</bold>
Male Wistar rats (200−300 g) were anesthetized with
urethane (1.4 g/mL in 20 mL in 0.9% saline, 20 mL/kg) and
their state of consciousness determined, using the cornea reflex
test and the limb retraction test. The rats were carefully
monitored throughout the procedure to ensure that anesthesia
was maintained.
</p>
<p>A small incision was made in the throat, and the trachea
was located, via blunt dissection of the surrounding connective
tissue. A 1.57 mm (I.D.) polythene tube cannula was inserted
and securely fastened. The jugular vein was also cannulated
with 0.58 mm (I.D.) tubing to allow iv administration of the
compounds. A syringe containing saline was attached to the
jugular cannula to act as a seal preventing air bubbles from
entering the vein. An incision was made along the midline of
the abdomen. The common bile duct was located and allowed
to dilate before a 0.58 mm (I.D.) cannula was inserted. Control
bile was obtained. The penis was ligated, to allow urine to be
collected during the experiment.
</p>
<p>The radiolabeled compounds had been made up in a vehicle
composed of 50% dimethyl sulfoxide (DMSO)−49% water−1%
citric acid. DMSO replaced the saline in the jugular cannula
to prevent the drug precipitating out of solution during dosing.
</p>
<p>A 500 μL Hamilton syringe was filled with either [<sup>3</sup>
H]AQ
or [<sup>3</sup>
H]ISQ (54 μmol/kg, 25 μCi/kg) and connected to the
cannula. The radiolabeled compounds were infused via the
jugular vein over a period of 30 min to prevent respiratory
depression caused by DMSO. Bile fractions were collected at
hourly intervals for 5 h from the start of dosing, All samples
were weighed and their weight recorded.
</p>
<p>After 5 h, any remaining urine was aspirated from the
bladder, and blood was collected via cardiac puncture with a
heparinized needle into a heparinized tube. The sample was
centrifuged to allow the plasma and red blood cells to be
separated (4000 rpm for 5 min). The volume of plasma was
recorded. Tissues (brain, heart, kidney, liver, lung, spleen, and
skin) were removed from the animal, rinsed in saline before
being placed in vials, and weighed. All samples were stored
at −80 °C until they were required for analysis.
</p>
<p><bold>Investigation of [</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H] AQ and [</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H] ISQ Remaining in
the Plasma after Dosing.</bold>
The animal was anesthetized and
the jugular vein cannulated as described above. To allow blood
samples to be taken regularly, the carotid artery was cannulated with 0.58 mm I.D. polythene tubing. The cannula was
attached to a heparinized saline syringe to prevent blood
escaping from the cannula and to prevent air bubbles from
entering the blood stream. The animals were dosed as described above, and the clock was started at the end of the
dosing period. Blood samples (300 μL) were collected at 15 min,
30 min, and hourly postdosing. Heparinized saline was flushed
through the cannula after every blood collection to prevent
clotting within the tubing. The saline was allowed to drain
out of the cannula prior to every collection point.
</p>
<p>After the fifth hour sample had been collected, all remaining
blood within the rat was allowed to drain from the cannula
into a heparinized tube. All samples were centrifuged (4000
rpm for 5 min) immediately after collection, and the pellet and
supernatant were separated. The volume of the plasma was
recorded. The tissues were also removed and weighed, and all
samples were stored at −80 °C until analyzed. The active
components of the plasma were removed via extraction with
ether for LC/MS analysis.
</p>
<p><bold>24 </bold>
<bold>h</bold>
<bold> Metabolism Study.</bold>
[<sup>3</sup>
H]AQ (54 μmol/kg) was administered ip to male Wistar rats (200−300 g). Each animal was
placed in a wire-bottom metabolism cage with access to food
and water. Urine was collected over 24 h, and the cage was
rinsed with distilled water (10 mL) at the end of the collection
period. After 24 h, the animals were anesthetized with
phenobarbitone (60 mg/kg in 0.9% saline) and their tissues
removed and blood collected via cardiac puncture with a
heparinized needle. All samples were stored at −80 °C until
analyzed. Previous ISQ data was obtained for comparison with
AQ. These data was produced following the same procedure
used for AQ.
</p>
<p><bold>Analysis of the Radioactivity Excreted into Urine,
Bile, and Plasma.</bold>
Aliquot of bile (2 × 10 μL), urine (2 × 50
μL), and plasma (2 × 50 μL) from animals dosed with [<sup>3</sup>
H]AQ
or [<sup>3</sup>
H]ISQ were added to 4 mL of liquid scintillant and
vortexed thoroughly. Samples were left in darkness overnight
to prevent chemiluminescence. Radioactivity was then determined using a Packard 1500 Liquid Scintillation Analyzer.
</p>
<p><bold>Investigation of the Tissue Distribution of [</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H]AQ or
[</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H]ISQ over 5 h.</bold>
Portions of each tissue (50−100 mg) and
aliquots of red blood cells (50−60 mg) were taken in duplicate,
and tissue solubilizer (0.5 mL) was added to each sample and
left overnight at 50 °C. The samples were cooled to room
temperature before being decolorized with hydrogen peroxide
(200 μL) and left for 1 h. The mixture was then neutralized
with glacial acetic acid (30 μL) and 12 mL of scintillation fluid
was added. The mixture was mixed thoroughly and left
overnight in the dark. The samples were assayed for radioactivity (all volumes of chemicals to be added were doubled for
solubulizing the red blood cells).
</p>
<p><bold>Analysis of Urinary, Biliary, and Plasma Metabolites
of Male Wistar Rats Dosed with </bold>
<bold>[</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H]AQ or [</bold>
<bold><sup>3</sup>
</bold>
<sup></sup>
<bold>H]ISQ.</bold>
Aliquots (50−100 μL) of bile, urine, and plasma ether extracts
were eluted from a Zorbax SB-18 column with a slow acetonitrile gradient (10−50% over 30 min) in ammonium acetate
(5.0 mM, pH 3.8) at 0.9 mL/min. Two Jasco PU-980 pumps
were linked to a mixing module, allowing effluent to mix with
scintillation fluid prior to reaching the Flo-One A250 beta
radioactive flow detector or allowing the effluent to be delivered to the Quattro II mass spectrometer. Nebulizing and
drying gas were delivered at a rate of 13 L/h and 300 L/h,
respectively. The temperature of the LC/MS interface was 70
°C, and the capillary voltage was 3.7 × 10<sup>-2</sup>
V. The extent of
fragmentation was modulated via altering the cone voltage.
</p>
</sec>
</body>
<back><ack><title>Acknowledgments</title>
<p>We thank the Medicines for
Malaria Venture (MMV), Geneva, the Wellcome Trust
(S.A.W., B.K.P.), the Leverhulme Trust (P.A.S.), GlaxoSmithkline Pharmaceuticals (S.A.W., PON, B.K.P.,
P.A.W.), and the EPSRC (A.M.) for funding this program. The authors also thank the Wellcome Trust for a
grant for a mass spectrometer, the EPSRC for a single-crystal diffractometer (GR/N36851 EPSRC), and NMR
facility (GR/M90801).
</p>
</ack>
<notes notes-type="si"><sec id="d7e4099"><title><ext-link xlink:href="/doi/suppl/10.1021%2Fjm030796n">Supporting Information Available</ext-link>
</title>
<p>X-ray crystallographic data and further details of metabolism studies on
isoquine. This material is available free of charge via the
Internet at <uri xlink:href="http://pubs.acs.org">http://pubs.acs.org</uri>
.
</p>
</sec>
</notes>
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<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Chemistry.</affiliation>
<affiliation> Department of Pharmacology and Therapeutics.</affiliation>
<affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</affiliation>
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<name type="personal"><namePart type="family">MUKHTAR</namePart>
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<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Chemistry.</affiliation>
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</name>
<name type="personal"><namePart type="family">STOCKS</namePart>
<namePart type="given">Paul A.</namePart>
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<affiliation> Department of Chemistry.</affiliation>
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</name>
<name type="personal"><namePart type="family">RANDLE</namePart>
<namePart type="given">Laura E.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Pharmacology and Therapeutics.</affiliation>
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</name>
<name type="personal"><namePart type="family">HINDLEY</namePart>
<namePart type="given">Stephen</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Chemistry.</affiliation>
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</name>
<name type="personal" displayLabel="corresp"><namePart type="family">WARD</namePart>
<namePart type="given">Stephen A.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Molecular and Biochemical Parasitology Group.</affiliation>
<affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</affiliation>
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<name type="personal"><namePart type="family">STORR</namePart>
<namePart type="given">Richard C.</namePart>
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<affiliation> Department of Chemistry.</affiliation>
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</name>
<name type="personal"><namePart type="family">BICKLEY</namePart>
<namePart type="given">Jamie F.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Chemistry.</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="family">O'NEIL</namePart>
<namePart type="given">Ian A.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Chemistry.</affiliation>
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</name>
<name type="personal"><namePart type="family">MAGGS</namePart>
<namePart type="given">James L.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Pharmacology and Therapeutics.</affiliation>
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</role>
</name>
<name type="personal"><namePart type="family">HUGHES</namePart>
<namePart type="given">Ruth H.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Molecular and Biochemical Parasitology Group.</affiliation>
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</role>
</name>
<name type="personal"><namePart type="family">WINSTANLEY</namePart>
<namePart type="given">Peter A.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Pharmacology and Therapeutics.</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="family">BRAY</namePart>
<namePart type="given">Patrick G.</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Molecular and Biochemical Parasitology Group.</affiliation>
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</role>
</name>
<name type="personal" displayLabel="corresp"><namePart type="family">PARK</namePart>
<namePart type="given">B. Kevin</namePart>
<affiliation>Department of Chemistry, The Robert Robinson Laboratories, University of Liverpool, Liverpool L69 7ZD, Department ofPharmacology and Therapeutics, University of Liverpool, Liverpool L69 3GE, UK, and Molecular and BiochemicalParasitology Group, Liverpool School of Tropical Medicine, University of Liverpool, Pembroke Place, Liverpool L3 5QA, UK</affiliation>
<affiliation> Department of Pharmacology and Therapeutics.</affiliation>
<affiliation> Authors for correspondence. (P.M.O.) Phone: 0151-794-3553.Fax: 0151-794-8218. E-mail: P.M.oneill01@liv.ac.uk. (B.K.P.) Phone: 0151-794-5559. E-mail: B.K.Park@liv.ac.uk. (S.A.W.). E-mail: saward@liv.ac.uk.</affiliation>
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<abstract>Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial that can cause adverse side effects including agranulocytosis and liver damage. The observed drug toxicity is believed to involve the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which can bind to cellular macromolecules and initiate hypersensitivity reactions. We proposed that interchange of the 3‘ hydroxyl and the 4‘ Mannich side-chain function of amodiaquine would provide a new series of analogues that cannot form toxic quinoneimine metabolites via cytochrome P450-mediated metabolism. By a simple two-step procedure, 10 isomeric amodiaquine analogues were prepared and subsequently examined against the chloroquine resistant K1 and sensitive HB3 strains of Plasmodium falciparum in vitro. Several analogues displayed potent antimalarial activity against both strains. On the basis of the results of in vitro testing, isoquine (ISQ1 (3a)) (IC50 = 6.01 nM ± 8.0 versus K1 strain), the direct isomer of amodiaquine, was selected for in vivo antimalarial assessment. The potent in vitro antimalarial activity of isoquine was translated into excellent oral in vivo ED50 activity of 1.6 and 3.7 mg/kg against the P. yoelii NS strain compared to 7.9 and 7.4 mg/kg for amodiaquine. Subsequent metabolism studies in the rat model demonstrated that isoquine does not undergo in vivo bioactivation, as evidenced by the complete lack of glutathione metabolites in bile. In sharp contrast to amodiaquine, isoquine (and Phase I metabolites) undergoes clearance by Phase II glucuronidation. On the basis of these promising initial studies, isoquine (ISQ1 (3a)) represents a new second generation lead worthy of further investigation as a cost-effective and potentially safer alternative to amodiaquine.</abstract>
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