AbstractBromo‐benzothiophene carboxamide derivatives have been shown in the preceding article to inhibit Plasmodium falciparum Enoyl‐ACP reductase. Here, we report bromo‐benzothiophene carboxamide derivatives as potent inhibitors of Plasmodium asexual blood‐stages in vitro as well as in vivo in the mouse model. These compounds specifically impair the development of metabolically active trophozoite stage of intraerythrocytic cycle and the intravenous administration of 3‐bromo‐N‐(4‐fluorobenzyl)‐benzo[b]thiophene‐2‐carboxamide (compound 6) enhances the longevity of P. berghei infected mice by 2 weeks compared to disease control animals thereby preventing the onset of ataxia and convulsions in treated mice. These compounds thus hold promise for the development of potent antimalarials. © 2011 IUBMB IUBMB Life, 63(12): 1111–1115, 2011