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

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
Journal:
Journal of medicinal chemistry, Volume: 64, Issue: 9
Published:
May 13, 2021
PMID:
33876936
Authors:
Michael J Palmer MJ, Xiaoyi Deng X, Shawn Watts S, Goran Krilov G, Aleksey Gerasyuto A, Sreekanth Kokkonda S, Farah El Mazouni F, John White J, Karen L White KL, Josefine Striepen J, Jade Bath J, Kyra A Schindler KA, Tomas Yeo T, David M Shackleford DM, Sachel Mok S, Ioanna Deni I, Aloysus Lawong A, Ann Huang A, Gong Chen G, Wen Wang W, Jaya Jayaseelan J, Kasiram Katneni K, Rahul Patil R, Jessica Saunders J, Shatrughan P Shahi SP, Rajesh Chittimalla R, Iñigo Angulo-Barturen I, María Belén Jiménez-Díaz MB, Sergio Wittlin S, Patrick K Tumwebaze PK, Philip J Rosenthal PJ, Roland A Cooper RA, Anna Caroline Campos Aguiar ACC, Rafael V C Guido RVC, Dhelio B Pereira DB, Nimisha Mittal N, Elizabeth A Winzeler EA, Diana R Tomchick DR, Benoît Laleu B, Jeremy N Burrows JN, Pradipsinh K Rathod PK, David A Fidock DA, Susan A Charman SA, Margaret A Phillips MA
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Abstract:

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 () 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 against blood and liver schizont stages and show good efficacy in SCID mouse models. They are equally active against and field isolates and are selective for DHODHs versus mammalian enzymes.

Courtesy of the U.S. National Library of Medicine