Synthesis and Antimalarial Activity of New Amino Analogues of Amodiaquine

E.      Paunescu; S.      Susplugas; E.      Boll; R.   A.   Varga; E.      Mouray; P.      Grellier; P.      Melnyk

Abstract

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.

Keywords: Antimalarials, 4-aminoquinolines, amodiaquine, Plasmodium falciparum