N10,N11-di-alkylamine indolo[3,2-b]quinolines as hemozoin inhibitors: design, synthesis and antiplasmodial activity

Bioorganic & Medicinal Chemistry
Marta FigueirasAlexandra Paulo

Abstract

We recently reported that potent N10,O11-bis-alkylamine indolo[3,2-b]quinoline antimalarials act as hemozoin (Hz) growth inhibitors. To improve access and binding to the target we have now designed novel N10,N11-di-alkylamine bioisosteres. 3-Chloro derivatives (10a-f) showed selectivity for malaria parasite compared to human cells, high activity against Plasmodium falciparum chloroquine (CQ)-resistant strain W2 (IC50s between 20 and 158nM), good correlation with β-hematin inhibition and improved vacuolar accumulation ratios, thus suggesting inhibition of Hz growth as one possible mechanism of action for these compounds. Moreover, our studies show that Hz is a valid target for the development of new antimalarials able to overcome CQ resistance.

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Citations

Dec 8, 2015·Journal of Medicinal Chemistry·Bogdan A ŠolajaDonatella Taramelli
Mar 8, 2017·Physical Chemistry Chemical Physics : PCCP·Inês F A MarizErmelinda M S Maçôas
Sep 17, 2019·European Journal of Medicinal Chemistry·Anudeep K NarulaLalit M Nainwal
Jan 27, 2021·Journal of Agricultural and Food Chemistry·Yong-Jia ChenChen Tang

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