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Synthesis and Antimalarial Activity of New Amino Analogues of Amodiaquine

[ Vol. 4 , Issue. 5 ]


E. Paunescu, S. Susplugas, E. Boll, R. A. Varga, E. Mouray, P. Grellier and P. Melnyk   Pages 407 - 425 ( 19 )


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.


Antimalarials, 4-aminoquinolines, amodiaquine, Plasmodium falciparum


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