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.

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.