Synthesis and Antimalarial Activity of New Amino Analogues of Amodiaquine

Title: Synthesis and Antimalarial Activity of New Amino Analogues of Amodiaquine

Volume: 4 Issue: 5

Author(s): E. Paunescu, S. Susplugas, E. Boll, R. A. Varga, E. Mouray, P. Grellier and P. Melnyk

Affiliation:

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

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.

Cite this article as:

Paunescu E., Susplugas S., Boll E., Varga A. R., Mouray E., Grellier P. and Melnyk P., Synthesis and Antimalarial Activity of New Amino Analogues of Amodiaquine, Medicinal Chemistry 2008; 4 (5) . https://dx.doi.org/10.2174/157340608785700153