| Literature DB >> 33620219 |
Aloysus Lawong1, Suraksha Gahalawat1, John Okombo2, Josefine Striepen2, Tomas Yeo2, Sachel Mok2, Ioanna Deni2, Jessica L Bridgford2, Hanspeter Niederstrasser1, Anwu Zhou1, Bruce Posner1, Sergio Wittlin3,4, Francisco Javier Gamo5, Benigno Crespo5, Alisje Churchyard6, Jake Baum6, Nimisha Mittal7, Elizabeth Winzeler7, Benoît Laleu8, Michael J Palmer8, Susan A Charman9, David A Fidock2,10, Joseph M Ready1, Margaret A Phillips1.
Abstract
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 Plasmodium falciparum 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 1 (pfmdr1). 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.Entities:
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Year: 2021 PMID： 33620219 PMCID： PMC7997635 DOI： 10.1021/acs.jmedchem.0c02022
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446