Novel Antimalarial Tetrazoles and Amides Active against the Hemoglobin Degradation Pathway in Plasmodium falciparum

11 Mar 2021

Lawong A, Gahalawat S, Okombo J, Striepen J, Yeo T, Mok S, Deni I, Bridgford JL, Niederstrasser H, Zhou A, Posner B, Wittlin S, Gamo FJ, Crespo B, Churchyard A, Baum J, Mittal N, Winzeler E, Laleu B, Palmer MJ, Charman SA, Fidock DA, Ready JM, Phillips MA

Journal of Medicinal Chemistry
PMID: 33620219

Doi: 10.1021/acs.jmedchem.0c02022

Photo: BrianAJackson/iStock

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene. Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.

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