Synthesis and antimalarial activity of new amino analogues of amodiaquine.

E Paunescu (1) , Sophie Susplugas (2) , E Boll , R A Varga , Elisabeth Mouray (2) , Philippe Grellier (2) , Patricia Melnyk (1)

1 IBLI - Institut de biologie de Lille - IBL
2 MCAM - Molécules de Communication et Adaptation des Micro-organismes

Amodiaquine remains one of the most prescribed antimalarial 4-aminoquinoline. To assess the importance of the 4'-hydroxyl group and subsequent hydrogen bond in the antimalarial activity of amodiaquine (AQ), a series of new analogues in which this functionality was replaced by various amino groups was synthesized. The incorporation of a 3'-pyrrolidinamino group instead of the 3'-diethylamino function of AQ allowed the development of a parallel series of amopyroquine derivatives. The compounds were screened against both chloroquine (CQ)-sensitive and -resistant strains of Plasmodium falciparum and their cytotoxicity evaluated upon the MRC5 cell line. Antimalarial activity in a low nanomolar range was recorded showing that the 4'-hydroxy function can be successfully replaced by various amino substituents in terms of activity without any influence of the level of CQ-resistance of the strains. Furthermore the ability of the compounds to inhibit beta-hematin formation was measured in order to discuss the mechanism of action of these new compounds. Compounds 7d and 8d exhibit a high selectivity index and may be considered as promising leads for further development.

Domaines: Chimie; Sciences du Vivant [q-bio]; Microbiologie et Parasitologie

E Paunescu, Sophie Susplugas, E Boll, R A Varga, Elisabeth Mouray, et al.. Synthesis and antimalarial activity of new amino analogues of amodiaquine.. Medicinal Chemistry, 2008, 4 (5), pp.405-427. ⟨10.2174/157340608785700153⟩. ⟨mnhn-02070086⟩