Replacement of the 4'-hydroxy group of amodiaquine and amopyroquine by aromatic and aliphatic substituents: synthesis and antimalarial 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 Csp(2)-Csp(2) and Csp(2)-Csp(3) 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 IC(50) 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 beta-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.
Păunescu
Emilia
E
UMR CNRS - Universités de Lille I & II - IPL, France.
Susplugas
Sophie
S
Boll
Emmanuelle
E
Varga
Richard
R
Mouray
Elisabeth
E
Grosu
Ion
I
Grellier
Philippe
P
Melnyk
Patricia
P
D000655:Amodiaquine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003460:Crystallization; D018360:Crystallography, X-Ray; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D004583:Electrons; D006801:Humans; D006900:Hydroxylation; D007097:Imines / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010963:Plasmodium falciparum / Q000187:drug effects
D000962:Antimalarials; D007097:Imines; D000655:Amodiaquine; D003577:Cytochrome P-450 Enzyme System