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

(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 μM against W2 and 3 μM against FCR3. Molecular modeling studies suggest that (1H-pyridin-4-ylidene)amines may bind to the ubiquinol oxidation Qo site of cytochrome bc1.

Graphical abstract(1H-Pyridin-4-ylidene)amines designed as clopidol isosteres were active against Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains in the low micromolar range.Figure optionsDownload full-size imageDownload as PowerPoint slide