Potent Antimalarials
with Development Potential Identified
by Structure-Guided Computational Optimization of a Pyrrole-Based
Dihydroorotate Dehydrogenase Inhibitor Series
posted on 2021-04-20, 13:35authored byMichael
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 Wang, Jaya 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
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.