Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.
Authors
Michael J. Palmer, Medicines for Malaria Venture
Xiaoyi Deng, University of Texas Southwestern Medical Center at Dallas
Shawn Watts, Schrodinger, Inc.
Goran Krilov, Schrodinger, Inc.
Aleksey Gerasyuto, Schrodinger, Inc.
Sreekanth Kokkonda, University of Washington - Seattle Campus
Farah El Mazouni, University of Texas Southwestern Medical Center at Dallas
John White, University of Washington - Seattle Campus
Karen L White, Monash University
Josefine Striepen, Columbia University Irving Medical Center
Jade Bath, Columbia University Irving Medical Center
Kyra A. Schindler, Columbia University Irving Medical Center
Tomas Yeo, Columbia University Irving Medical CenterFollow
David M. Shackleford, Monash University
Sachel Mok, Columbia University Irving Medical CenterFollow
Ioanna Deni, Columbia University Irving Medical Center
Aloysus Lawong, University of Texas Southwestern Medical Center at Dallas
Ann Huang, University of Texas Southwestern Medical Center at Dallas
Gong Chen, Monash University
Wen Wang, Monash University
Jaya Jayaseelan, Monash University
Kasiram Katneni, Monash University
Rahul Patil, Monash University
Jessica Saunders, Monash University
Shatrughan P. Shahi, Syngene International Ltd
Rajesh Chittimalla, Syngene International Ltd
Iñigo Angulo-Barturen, TAD
María Belén Jiménez-Díaz, TADFollow
Sergio Wittlin, Swiss Tropical and Public Health Institute
Patrick K. Tumwebaze, Infectious Diseases Research CollaborationFollow
Philip J. Rosenthal, University of California, San FranciscoFollow
Roland A. Cooper, Dominican University of CaliforniaFollow
Anna Caroline Campos Aguiar, University of Sao Paulo, Brazil
Rafael V C Guido, University of Sao Paulo, BrazilFollow
Dhelio B. Pereira, Tropical Medicine Research Center of Rondonia
Nimisha Mittal, University of California San Diego
Elizabeth A Winzeler, University of California San Diego, La Jolla
Diana R. Tomchick, University of Texas Southwestern Medical Center at Dallas
Benoît Laleu, Medicines for Malaria Venture
Jeremy N. Burrows, Medicines for Malaria Venture
Pradipsinh K Rathod, University of Washington - Seattle Campus
David A. Fidock, Columbia University Irving Medical CenterFollow
Susan A. Charman, Columbia University Irving Medical Center
Margaret A. Phillips, University of Texas Southwestern Medical Center at Dallas
Department
Natural Sciences and Mathematics
Source
Journal of Medicinal Chemistry
Publication Date
5-13-2021
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.
