Journal article
Discovery and development of 2-aminobenzimidazoles as potent antimalarials
SM Devine, MP Challis, JK Kigotho, G Siddiqui, A De Paoli, CA MacRaild, VM Avery, DJ Creek, RS Norton, PJ Scammells
European Journal of Medicinal Chemistry | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Published : 2021
Abstract
The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC50 values against P. falciparum 3D7 strain of 42 ± 4 (3c) and 43 ± 2 nM (3g), and high potency against strains resistant to chloroquine (Dd2), artemisinin (Cam3.IIC580Y) and PfATP4 inhibitors (SJ557733), while demonstrating no cytotoxicity against human cells (HEK293, IC50 > 50 μM). The most pote..
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Grants
Awarded by National Health and Medical Research Council
Funding Acknowledgements
The authors would like to thank Ben Capuano for productive discussions on this project, Jason Dang for obtaining HRMS data and the Australian Red Cross Blood Service for the provision of human red blood cells. This work was supported in part by Australian National Health and Medical Research Council (NHMRC) Project (1098884 & 1163235) and Synergy grants (1185354). R. S. N. and D. J. C. acknowledge fellowship support from the NHMRC. The Centre for Drug Candidate Optimisation (CDCO, Monash University) is acknowledged for conducting the ADME studies. The CDCO is partially supported by the Monash University Technology Research Platform network and Therapeutic Innovation Australia (TIA) through the Australian Government National Collaborative Research Infrastructure Strategy (NCRIS) program.