Replacement of the 4′‐Hydroxy Group of Amodiaquine and Amopyroquine by Aromatic and Aliphatic Substituents: Synthesis and Antimalarial Activity
Identifieur interne : 001E41 ( Istex/Curation ); précédent : 001E40; suivant : 001E42Replacement of the 4′‐Hydroxy Group of Amodiaquine and Amopyroquine by Aromatic and Aliphatic Substituents: Synthesis and Antimalarial Activity
Auteurs : Emilia P Unescu [Roumanie] ; Sophie Susplugas [France] ; Emmanuelle Boll ; Richard Varga [Roumanie] ; Elisabeth Mouray [France] ; Ion Grosu [Roumanie] ; Philippe Grellier [France] ; Patricia Melnyk [France]Source :
- ChemMedChem [ 1860-7179 ] ; 2009-04-17.
Abstract
4′‐Substituted analogues of amodiaquine and amopyroquine were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM; one compound showed in vivo activity. The prophylactic administration of amodiaquine (AQ), a 4‐aminoquinoline antimalarial drug, has been associated with side effects such as agranulocytosis and liver damage. The toxicity of this drug is mediated by amodiaquine quinone‐imine, an electrophilic metabolite. Replacement of the 4′‐hydroxy function of AQ with various alkyl, aryl, or heteroaryl substituents would provide analogues that avoid metabolism to potentially toxic derivatives. Following a multistep procedure, 33 compounds containing hydrophobic groups at the 4′‐position were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM. Alkyl analogues are more efficient than aryl or heteroaryl derivatives. All compounds were also assessed for their cytotoxicity and ability to inhibit β‐hematin formation in vitro. A detailed investigation of the structure–activity relationships for these new compounds was carried out; the 4′‐methyl compound showed interesting in vivo antimalarial activity.
4′‐Substituted analogues of amodiaquine and amopyroquine were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM; one compound showed in vivo activity.
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DOI: 10.1002/cmdc.200800318
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Emmanuelle Boll<affiliation><mods:affiliation>UMR CNRS 8161 – Universités de Lille I & II – IPL, 1 rue du Prof. Calmette, BP 447, 59021 Lille cedex (France), Fax: (+33) 3 20 87 12 35</mods:affiliation><wicri:noCountry code="subField">(+33) 3 20 87 12 35</wicri:noCountry></affiliation>Le document en format XML
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No. 11</wicri:regionArea></affiliation></author><author><name sortKey="Susplugas, Sophie" sort="Susplugas, Sophie" uniqKey="Susplugas S" first="Sophie" last="Susplugas">Sophie Susplugas</name><affiliation wicri:level="1"><mods:affiliation>USM 0504‐EA 3335 Muséum National d'Histoire Naturelle, Département Régulations, Développement, Diversité Moléculaire, CP 52, 61 rue Buffon, 75005 Paris (France)</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>USM 0504‐EA 3335 Muséum National d'Histoire Naturelle, Département Régulations, Développement, Diversité Moléculaire, CP 52, 61 rue Buffon</wicri:regionArea></affiliation></author><author><name sortKey="Boll, Emmanuelle" sort="Boll, Emmanuelle" uniqKey="Boll E" first="Emmanuelle" last="Boll">Emmanuelle Boll</name><affiliation><mods:affiliation>UMR CNRS 8161 – Universités de Lille I & II – IPL, 1 rue du Prof. Calmette, BP 447, 59021 Lille cedex (France), Fax: (+33) 3 20 87 12 35</mods:affiliation><wicri:noCountry code="subField">(+33) 3 20 87 12 35</wicri:noCountry></affiliation></author><author><name sortKey="Varga, Richard" sort="Varga, Richard" uniqKey="Varga R" first="Richard" last="Varga">Richard Varga</name><affiliation wicri:level="1"><mods:affiliation>National Centre for X‐Ray Diffractometry, “Babes‐Bolyai” University, Faculty of Chemistry and Chemical Engineering, Arany Janos Str. No. 11, 400028 Cluj‐Napoca (Romania)</mods:affiliation><country xml:lang="fr">Roumanie</country><wicri:regionArea>National Centre for X‐Ray Diffractometry, “Babes‐Bolyai” University, Faculty of Chemistry and Chemical Engineering, Arany Janos Str. No. 11</wicri:regionArea></affiliation></author><author><name sortKey="Mouray, Elisabeth" sort="Mouray, Elisabeth" uniqKey="Mouray E" first="Elisabeth" last="Mouray">Elisabeth Mouray</name><affiliation wicri:level="1"><mods:affiliation>USM 0504‐EA 3335 Muséum National d'Histoire Naturelle, Département Régulations, Développement, Diversité Moléculaire, CP 52, 61 rue Buffon, 75005 Paris (France)</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>USM 0504‐EA 3335 Muséum National d'Histoire Naturelle, Département Régulations, Développement, Diversité Moléculaire, CP 52, 61 rue Buffon</wicri:regionArea></affiliation></author><author><name sortKey="Grosu, Ion" sort="Grosu, Ion" uniqKey="Grosu I" first="Ion" last="Grosu">Ion Grosu</name><affiliation wicri:level="1"><mods:affiliation>Organic Chemistry Department, “Babes‐Bolyai” University, Faculty of Chemistry and Chemical Engineering, Arany Janos Str. No. 11, 400028 Cluj‐Napoca (Romania)</mods:affiliation><country xml:lang="fr">Roumanie</country><wicri:regionArea>Organic Chemistry Department, “Babes‐Bolyai” University, Faculty of Chemistry and Chemical Engineering, Arany Janos Str. No. 11</wicri:regionArea></affiliation></author><author><name sortKey="Grellier, Philippe" sort="Grellier, Philippe" uniqKey="Grellier P" first="Philippe" last="Grellier">Philippe Grellier</name><affiliation wicri:level="1"><mods:affiliation>USM 0504‐EA 3335 Muséum National d'Histoire Naturelle, Département Régulations, Développement, Diversité Moléculaire, CP 52, 61 rue Buffon, 75005 Paris (France)</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>USM 0504‐EA 3335 Muséum National d'Histoire Naturelle, Département Régulations, Développement, Diversité Moléculaire, CP 52, 61 rue Buffon</wicri:regionArea></affiliation></author><author><name sortKey="Melnyk, Patricia" sort="Melnyk, Patricia" uniqKey="Melnyk P" first="Patricia" last="Melnyk">Patricia Melnyk</name><affiliation><mods:affiliation>UMR CNRS 8161 – Universités de Lille I & II – IPL, 1 rue du Prof. Calmette, BP 447, 59021 Lille cedex (France), Fax: (+33) 3 20 87 12 35</mods:affiliation></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: patricia.melnyk@ibl.fr</mods:affiliation><country wicri:rule="url">France</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">ChemMedChem</title><title level="j" type="alt">CHEMMEDCHEM</title><idno type="ISSN">1860-7179</idno><idno type="eISSN">1860-7187</idno><imprint><biblScope unit="vol">4</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="549">549</biblScope><biblScope unit="page" to="561">561</biblScope><biblScope unit="page-count">13</biblScope><publisher>WILEY‐VCH Verlag</publisher><pubPlace>Weinheim</pubPlace><date type="published" when="2009-04-17">2009-04-17</date></imprint><idno type="ISSN">1860-7179</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1860-7179</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">4′‐Substituted analogues of amodiaquine and amopyroquine were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM; one compound showed in vivo activity. The prophylactic administration of amodiaquine (AQ), a 4‐aminoquinoline antimalarial drug, has been associated with side effects such as agranulocytosis and liver damage. The toxicity of this drug is mediated by amodiaquine quinone‐imine, an electrophilic metabolite. Replacement of the 4′‐hydroxy function of AQ with various alkyl, aryl, or heteroaryl substituents would provide analogues that avoid metabolism to potentially toxic derivatives. Following a multistep procedure, 33 compounds containing hydrophobic groups at the 4′‐position were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM. Alkyl analogues are more efficient than aryl or heteroaryl derivatives. All compounds were also assessed for their cytotoxicity and ability to inhibit β‐hematin formation in vitro. A detailed investigation of the structure–activity relationships for these new compounds was carried out; the 4′‐methyl compound showed interesting in vivo antimalarial activity.</div><div type="abstract" xml:lang="en">4′‐Substituted analogues of amodiaquine and amopyroquine were synthesized using Csp2–Csp2 and Csp2–Csp3 Suzuki–Miyaura cross‐coupling reactions as the key step. The new derivatives were found to be active against both chloroquine (CQ)‐sensitive and CQ‐resistant strains of P. falciparum, with IC50 values in the range of 7–200 nM; one compound showed in vivo activity.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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