Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series
Michael Palmer, Xiaoyi Deng, Shawn Watts, Goran Krilov, Aleksey I. 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 K. Lawong, Ann Yehong Huang, Gong Chen, Wen Wang, Jaya Jayaseelan, Kasiram Katneni, Rahul Patil, Jessica Saunders, Shatrughan P. Shahi, Rajesh Chittimalla, Íñigo Angulo‐Barturen, Marı́a Belén Jiménez-Dı́az, Sergio Wittlin, Patrick K. Tumwebaze, Philip J. Rosenthal, Roland A. Cooper, Anna Caroline Campos Aguiar, Rafael V. C. Guido, Dhélio B. Pereira, Nimisha Mittal, Elizabeth A. Winzeler, Diana R. Tomchick, Benoı̂t Laleu, Jeremy N. Burrows, Pradipsinh K. Rathod, David A. Fidock, Susan A. Charman, Margaret A. Phillips
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.