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

doi:10.1021/acsomega.8b01573

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 journal › Article › peer-review

21 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 language	English (US)
Pages (from-to)	9227-9240
Number of pages	14
Journal	ACS Omega
Volume	3
Issue number	8
DOIs	https://doi.org/10.1021/acsomega.8b01573
State	Published - Aug 31 2018

ASJC Scopus subject areas

General Chemistry
General Chemical Engineering

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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

Kokkonda, S, El Mazouni, F, White, KL, White, J, Shackleford, DM, Lafuente-Monasterio, MJ, Rowland, P, Manjalanagara, K, Joseph, JT, Garcia-Pérez, A, Fernandez, J, Gamo, FJ, Waterson, D, Burrows, JN, Palmer, MJ, Charman, SA, Rathod, PK & Phillips, MA 2018, 'Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity', ACS Omega, vol. 3, no. 8, pp. 9227-9240. https://doi.org/10.1021/acsomega.8b01573

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title = "Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity",

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.",

author = "Sreekanth Kokkonda and {El Mazouni}, Farah and White, {Karen L.} and John White and Shackleford, {David M.} and Lafuente-Monasterio, {Maria Jose} and Paul Rowland and Krishne Manjalanagara and Joseph, {Jayan T.} and Adolfo Garcia-P{\'e}rez and Jorge Fernandez and Gamo, {Francisco Javier} and David Waterson and Burrows, {Jeremy N.} and Palmer, {Michael J.} and Charman, {Susan A.} and Rathod, {Pradipsinh K.} and Phillips, {Margaret A.}",

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AU - Shackleford, David M.

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AU - Gamo, Francisco Javier

AU - Waterson, David

AU - Burrows, Jeremy N.

AU - Palmer, Michael J.

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AU - Rathod, Pradipsinh K.

AU - Phillips, Margaret A.

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

Abstract

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