Replacement of the 4′‐Hydroxy Group of Amodiaquine and Amopyroquine by Aromatic and Aliphatic Substituents: Synthesis and Antimalarial Activity
Identifieur interne : 000277 ( France/Analysis ); précédent : 000276; suivant : 000278Replacement 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
Affiliations:
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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><affiliations><list><country><li>France</li><li>Roumanie</li></country></list><tree><noCountry><name sortKey="Boll, Emmanuelle" sort="Boll, Emmanuelle" uniqKey="Boll E" first="Emmanuelle" last="Boll">Emmanuelle Boll</name></noCountry><country name="Roumanie"><noRegion><name sortKey="P Unescu, Emilia" sort="P Unescu, Emilia" uniqKey="P Unescu E" first="Emilia" last="P Unescu">Emilia P Unescu</name></noRegion><name sortKey="Grosu, Ion" sort="Grosu, Ion" uniqKey="Grosu I" first="Ion" last="Grosu">Ion Grosu</name><name sortKey="Varga, Richard" sort="Varga, Richard" uniqKey="Varga R" first="Richard" last="Varga">Richard Varga</name></country><country name="France"><noRegion><name sortKey="Susplugas, Sophie" sort="Susplugas, Sophie" uniqKey="Susplugas S" first="Sophie" last="Susplugas">Sophie Susplugas</name></noRegion><name sortKey="Grellier, Philippe" sort="Grellier, Philippe" uniqKey="Grellier P" first="Philippe" last="Grellier">Philippe Grellier</name><name sortKey="Melnyk, Patricia" sort="Melnyk, Patricia" uniqKey="Melnyk P" first="Patricia" last="Melnyk">Patricia Melnyk</name><name sortKey="Mouray, Elisabeth" sort="Mouray, Elisabeth" uniqKey="Mouray E" first="Elisabeth" last="Mouray">Elisabeth Mouray</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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