Design, synthesis and structure-activity relationships of (1H-pyridin-4-ylidene)amines as potential antimalarials

Abstract

(1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were prepared as potential clopidol isosteres in the development of antimalarials. Their antiplasmodial activity was evaluated in vitro against the Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains. The most active of these derivatives, 4m, had an IC50 of 1 mu M against W2 and 3 mu M against FCR3. Molecular modeling studies suggest that (1H-pyridin-4-ylidene) amines may bind to the ubiquinol oxidation Q(o) site of cytochrome bc(1). (C) 2009 Elsevier Ltd. All rights reserved.. - Funda ao para a Ciencia e Tecnologia (FCT, Portugal) ; Doris Duke Charitable Foundation Distinguished Clinical Scientist [SFRH/BD/30689/2006]. - This work was supported by Funda ao para a Ciencia e Tecnologia (FCT, Portugal); T. R. acknowledges FCT for the Ph. D. grant SFRH/BD/30689/2006. P.J.R. is a Doris Duke Charitable Foundation Distinguished Clinical Scientist.