Orally Effective Aminoalkyl 10H-Indolo-[3,2-b]quinoline-11-carboxamide Kills the Malaria Parasite by Inhibiting Host Hemoglobin Uptake.

A series of indolo[3,2-b]quinoline-C11-carboxamides were synthesized by incorporation of amino-alkyl side chains into the core of indolo[3,2-b]quinoline-C11-carboxylic acid. Their in vitro antiplasmodial evaluation against Plasmodium falciparum has led to the identification of 2-(piperidin-1-yl)ethanamine linked analog [2-bromo-N-(2-(piperidin-1-yl)ethyl)-10H-indolo[3,2-b]quinoline-11-carboxamide, 3g] (IC50 1.3 µM) as the most promising compound exhibiting good selectivity-indices against mammalian cell lines. The kill-kinetics on erythrocytic-stage parasites revealed that 3g causes complete killing of only the trophozoite-stage parasites. Mechanistic studies have shown that 3g targets the food vacuole of parasite, and inhibits the hemoglobin uptake, β-haematin formation and basic endocytic processes of the parasite. Analog 3g was found to be orally bioavailable and its curative antimalarial studies at 50 mg/kg, p.o. against Plasmodium berghei (ANKA)-infected mouse model showed that the 3g-treated mice showed 27-35% suppression of parasitemia with increased life-span of treated as compared to untreated-control mice. Thus, the present work has demonstrated a proof-of-concept for oral efficacy of indolo[3,2-b]quinoline-C11-carboxamides.