Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series

Michael J. Palmer, Xiaoyi Deng, Shawn Watts, Goran Krilov, Aleksey Gerasyuto, Sreekanth Kokkonda, Farah El Mazouni, John White, Karen L. White, Josefine Striepen, Jade Bath, Kyra A. Schindler, Tomas Yeo, David M. Shackleford, Sachel Mok, Ioanna Deni, Aloysus Lawong, Ann Huang, Gong Chen, Wen WangJaya Jayaseelan, Kasiram Katneni, Rahul Patil, Jessica Saunders, Shatrughan P. Shahi, Rajesh Chittimalla, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Sergio Wittlin, Patrick K. Tumwebaze, Philip J. Rosenthal, Roland A. Cooper, Anna Caroline Campos Aguiar, Rafael V.C. Guido, Dhelio B. Pereira, Nimisha Mittal, Elizabeth A. Winzeler, Diana R. Tomchick, Benoît Laleu, Jeremy N. Burrows, Pradipsinh K. Rathod, David A. Fidock, Susan A. Charman, Margaret A. Phillips

Research output: Contribution to journalArticlepeer-review

Abstract

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.

Original languageEnglish (US)
Pages (from-to)6085-6136
Number of pages52
JournalJournal of Medicinal Chemistry
Volume64
Issue number9
DOIs
StatePublished - May 13 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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