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

J Med Chem. 2021 Mar 11;64(5):2739-2761. doi: 10.1021/acs.jmedchem.0c02022.

Aloysus Lawong ¹, Suraksha Gahalawat ¹, John Okombo ², Josefine Striepen ², Tomas Yeo ², Sachel Mok ², Ioanna Deni ², Jessica L Bridgford ², Hanspeter Niederstrasser ¹, Anwu Zhou ¹, Bruce Posner ¹, Sergio Wittlin ³ ⁴, Francisco Javier Gamo ⁵, Benigno Crespo ⁵, Alisje Churchyard ⁶, Jake Baum ⁶, Nimisha Mittal ⁷, Elizabeth Winzeler ⁷, Benoît Laleu ⁸, Michael J Palmer ⁸, Susan A Charman ⁹, David A Fidock ² ¹⁰, Joseph M Ready ¹, Margaret A Phillips ¹

Affiliations

1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
2 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
3 Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland.
4 University of Basel, 4002 Basel, Switzerland.
5 Medicines Development Campus, GlaxoSmithKline, Tres Cantos, 28760 Madrid, Spain.
6 Department of Life Sciences, Imperial College London, SW7 2AZ South Kensington, U.K.
7 Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California San Diego, La Jolla, California 92093, United States.
8 Medicines for Malaria Venture, 1215 Geneva, Switzerland.
9 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
10 Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.

PMID: 33620219 DOI: 10.1021/acs.jmedchem.0c02022

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.

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