Ramesh Mudududdla, D. Mohanakrishnan, Sonali S. Bharate
Nov 13, 2018
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Influential Citations
8
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Quality indicators
Journal
ChemMedChem
Abstract
A series of indolo[3,2‐b]quinoline‐C11‐carboxamides were synthesized by incorporation of aminoalkyl side chains into the core of indolo[3,2‐b]quinoline‐C11‐carboxylic acid. Their in vitro antiplasmodial evaluation against Plasmodium falciparum led to the identification of a 2‐(piperidin‐1‐yl)ethanamine‐linked analogue {2‐bromo‐N‐[2‐(piperidin‐1‐yl)ethyl]‐10H‐indolo[3,2‐b]quinoline‐11‐carboxamide (3 g)} (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 3 g caused complete killing of only the trophozoite‐stage parasites. Mechanistic studies showed that 3 g targets the food vacuole of the parasite and inhibits hemoglobin uptake, β‐hematin formation, and the basic endocytic processes of the parasite. Analogue 3 g was found to be orally bioavailable, and its curative antimalarial studies at 50 mg per kg p.o. against a Plasmodium berghei (ANKA)‐infected mouse model revealed that mice treated with 3 g showed 27–35 % suppression of parasitemia with an increase in life span relative to untreated, control mice. Thus, the present work demonstrated a proof of concept for the oral efficacy of indolo[3,2‐b]quinoline‐C11‐carboxamides.