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

Aloysus Lawong, Suraksha Gahalawat, John Okombo, Josefine Striepen, Tomas Yeo, Sachel Mok, Ioanna Deni, Jessica L. Bridgford, Hanspeter Niederstrasser, Anwu Zhou, Bruce Posner, Sergio Wittlin, Francisco Javier Gamo, Benigno Crespo, Alisje Churchyard, Jake Baum, Nimisha Mittal, Elizabeth Winzeler, Benoît Laleu, Michael J. PalmerSusan A. Charman, David A. Fidock, Joseph M. Ready, Margaret A. Phillips

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2739-2761
Number of pages23
JournalJournal of Medicinal Chemistry
Volume64
Issue number5
DOIs
StatePublished - Mar 11 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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