Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity

Sreekanth Kokkonda, Farah El Mazouni, Karen L. White, John White, David M. Shackleford, Maria Jose Lafuente-Monasterio, Paul Rowland, Krishne Manjalanagara, Jayan T. Joseph, Adolfo Garcia-Pérez, Jorge Fernandez, Francisco Javier Gamo, David Waterson, Jeremy N. Burrows, Michael J. Palmer, Susan A. Charman, Pradipsinh K. Rathod, Margaret A. Phillips

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Malaria kills nearly 0.5 million people yearly and impacts the lives of those living in over 90 countries where it is endemic. The current treatment programs are threatened by increasing drug resistance. Dihydroorotate dehydrogenase (DHODH) is now clinically validated as a target for antimalarial drug discovery as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. We discovered a related isoxazolopyrimidine series in a phenotypic screen, later determining that it targeted DHODH. To determine if the isoxazolopyrimidines could yield a drug candidate, we initiated hit-to-lead medicinal chemistry. Several potent analogues were identified, including a compound that showed in vivo antimalarial activity. The isoxazolopyrimidines were more rapidly metabolized than their triazolopyrimidine counterparts, and the pharmacokinetic data were not consistent with the goal of a single-dose treatment for malaria.

Original languageEnglish (US)
Pages (from-to)9227-9240
Number of pages14
JournalACS Omega
Volume3
Issue number8
DOIs
StatePublished - Aug 31 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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    Kokkonda, S., El Mazouni, F., White, K. L., White, J., Shackleford, D. M., Lafuente-Monasterio, M. J., Rowland, P., Manjalanagara, K., Joseph, J. T., Garcia-Pérez, A., Fernandez, J., Gamo, F. J., Waterson, D., Burrows, J. N., Palmer, M. J., Charman, S. A., Rathod, P. K., & Phillips, M. A. (2018). Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity. ACS Omega, 3(8), 9227-9240. https://doi.org/10.1021/acsomega.8b01573