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

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

  • J Med Chem. 2021 May 13;64(9):6085-6136. doi: 10.1021/acs.jmedchem.1c00173.
Michael J Palmer 1,  Xiaoyi Deng 2,  Shawn Watts 3,  Goran Krilov 3,  Aleksey Gerasyuto 3,  Sreekanth Kokkonda 4,  Farah El Mazouni 2,  John White 4,  Karen L White 5,  Josefine Striepen 6,  Jade Bath 6,  Kyra A Schindler 6,  Tomas Yeo 6,  David M Shackleford 5,  Sachel Mok 6,  Ioanna Deni 6,  Aloysus Lawong 2,  Ann Huang 2,  Gong Chen 5,  Wen Wang 5,  Jaya Jayaseelan 5,  Kasiram Katneni 5,  Rahul Patil 5,  Jessica Saunders 5,  Shatrughan P Shahi 7,  Rajesh Chittimalla 7,  Iñigo Angulo-Barturen 8,  María Belén Jiménez-Díaz 8,  Sergio Wittlin 9 10,  Patrick K Tumwebaze 11,  Philip J Rosenthal 12,  Roland A Cooper 13,  Anna Caroline Campos Aguiar 14,  Rafael V C Guido 14,  Dhelio B Pereira 15,  Nimisha Mittal 16,  Elizabeth A Winzeler 16,  Diana R Tomchick 2,  Benoît Laleu 1,  Jeremy N Burrows 1,  Pradipsinh K Rathod 4,  David A Fidock 6 17,  Susan A Charman 5,  Margaret A Phillips 2
Affiliations

Affiliations

  • 1 Medicines for Malaria Venture, 1215 Geneva, Switzerland.
  • 2 Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9135, United States.
  • 3 Schrodinger, Inc., 120 West 45th St, 17th Floor, New York, New York 100036-4041, United States.
  • 4 Departments of Chemistry and Global Health, University of Washington, Seattle, Washington 98195, United States.
  • 5 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
  • 6 Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 7 Syngene International Ltd, Bangalore 560099, India.
  • 8 TAD, Biscay Science and Technology Park, Astondo Bidea, BIC Bizkaia Bd 612, Derio, 48160 Bizkaia, Basque Country, Spain.
  • 9 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland.
  • 10 University of Basel, 4002 Basel, Switzerland.
  • 11 Infectious Diseases Research Collaboration, Kampala, Uganda.
  • 12 Department of Medicine, University of California, San Francisco, California 94143, United States.
  • 13 Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California 94901, United States.
  • 14 University of Sao Paulo, Sao Carlos Institute of Physics, Sáo Carlos, SP 13560-970, Brazil.
  • 15 Tropical Medicine Research Center of Rondonia, Av. Guaporé, 215, Porto Velho, RO 76812-329, Brazil.
  • 16 Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, School of Medicine, University of California San Diego, La Jolla, California 92093, United States.
  • 17 Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York 10032, United States.
PMID: 33876936 DOI: 10.1021/acs.jmedchem.1c00173
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.

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