Isoquine and Related Amodiaquine Analogues: A New Generation of Improved 4-Aminoquinoline Antimalarials
Identifieur interne : 002041 ( Main/Exploration ); précédent : 002040; suivant : 002042Isoquine and Related Amodiaquine Analogues: A New Generation of Improved 4-Aminoquinoline Antimalarials
Auteurs : Paul M. O'Neill [Royaume-Uni] ; Amira Mukhtar [Royaume-Uni] ; Paul A. Stocks [Royaume-Uni] ; Laura E. Randle [Royaume-Uni] ; Stephen Hindley [Royaume-Uni] ; Stephen A. Ward [Royaume-Uni] ; Richard C. Storr [Royaume-Uni] ; Jamie F. Bickley [Royaume-Uni] ; Ian A. O'Neil [Royaume-Uni] ; James L. Maggs [Royaume-Uni] ; Ruth H. Hughes [Royaume-Uni] ; Peter A. Winstanley [Royaume-Uni] ; Patrick G. Bray [Royaume-Uni] ; B. Kevin Park [Royaume-Uni]Source :
- 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
Affiliations:
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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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><affiliation></affiliation><affiliation></affiliation><affiliation></affiliation></author><author><name sortKey="Mukhtar, Amira" sort="Mukhtar, Amira" uniqKey="Mukhtar A" first="Amira" last="Mukhtar">Amira Mukhtar</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><affiliation></affiliation></author><author><name sortKey="Hindley, Stephen" sort="Hindley, Stephen" uniqKey="Hindley S" first="Stephen" last="Hindley">Stephen Hindley</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><affiliation></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><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 wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Liverpool L3 5QA</wicri:noRegion></affiliation><affiliation></affiliation><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></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2623</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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></TEI><affiliations><list><country><li>Royaume-Uni</li></country></list><tree><country name="Royaume-Uni"><noRegion><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></noRegion><name sortKey="Bickley, Jamie F" sort="Bickley, Jamie F" uniqKey="Bickley J" first="Jamie F." last="Bickley">Jamie F. Bickley</name><name sortKey="Bray, Patrick G" sort="Bray, Patrick G" uniqKey="Bray P" first="Patrick G." last="Bray">Patrick G. Bray</name><name sortKey="Hindley, Stephen" sort="Hindley, Stephen" uniqKey="Hindley S" first="Stephen" last="Hindley">Stephen Hindley</name><name sortKey="Hughes, Ruth H" sort="Hughes, Ruth H" uniqKey="Hughes R" first="Ruth H." last="Hughes">Ruth H. Hughes</name><name sortKey="Maggs, James L" sort="Maggs, James L" uniqKey="Maggs J" first="James L." last="Maggs">James L. Maggs</name><name sortKey="Mukhtar, Amira" sort="Mukhtar, Amira" uniqKey="Mukhtar A" first="Amira" last="Mukhtar">Amira Mukhtar</name><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><name sortKey="Park, B Kevin" sort="Park, B Kevin" uniqKey="Park B" first="B. Kevin" last="Park">B. Kevin Park</name><name sortKey="Randle, Laura E" sort="Randle, Laura E" uniqKey="Randle L" first="Laura E." last="Randle">Laura E. Randle</name><name sortKey="Stocks, Paul A" sort="Stocks, Paul A" uniqKey="Stocks P" first="Paul A." last="Stocks">Paul A. Stocks</name><name sortKey="Storr, Richard C" sort="Storr, Richard C" uniqKey="Storr R" first="Richard C." last="Storr">Richard C. Storr</name><name sortKey="Ward, Stephen A" sort="Ward, Stephen A" uniqKey="Ward S" first="Stephen A." last="Ward">Stephen A. Ward</name><name sortKey="Winstanley, Peter A" sort="Winstanley, Peter A" uniqKey="Winstanley P" first="Peter A." last="Winstanley">Peter A. Winstanley</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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