Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria

Sreekanth Kokkonda, Xiaoyi Deng, Karen L. White, Farah El Mazouni, John White, David M. Shackleford, Kasiram Katneni, Francis C.K. Chiu, Helena Barker, Jenna Mclaren, Elly Crighton, Gong Chen, Inigo Angulo-Barturen, Maria Belen Jimenez-Diaz, Santiago Ferrer, Leticia Huertas-Valentin, Maria Santos Martinez-Martinez, Maria Jose Lafuente-Monasterio, Rajesh Chittimalla, Shatrughan P. ShahiSergio Wittlin, David Waterson, Jeremy N. Burrows, Dave Matthews, Diana Tomchick, Pradipsinh K. Rathod, Michael J. Palmer, Susan A. Charman, Margaret A. Phillips

Research output: Contribution to journalArticle

Abstract

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.

Original languageEnglish (US)
Pages (from-to)4929-4956
Number of pages28
JournalJournal of Medicinal Chemistry
Volume63
Issue number9
DOIs
StatePublished - May 14 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Kokkonda, S., Deng, X., White, K. L., El Mazouni, F., White, J., Shackleford, D. M., Katneni, K., Chiu, F. C. K., Barker, H., Mclaren, J., Crighton, E., Chen, G., Angulo-Barturen, I., Jimenez-Diaz, M. B., Ferrer, S., Huertas-Valentin, L., Martinez-Martinez, M. S., Lafuente-Monasterio, M. J., Chittimalla, R., ... Phillips, M. A. (2020). Lead optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series for the treatment of malaria. Journal of Medicinal Chemistry, 63(9), 4929-4956. https://doi.org/10.1021/acs.jmedchem.0c00311