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, 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 journalArticleResearchpeer-review

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
Pages (from-to)9227-9240
Number of pages14
JournalACS Omega
Volume3
Issue number8
DOIs
Publication statusPublished - Aug 2018

Cite this

Kokkonda, S., El Mazouni, F., White, K. L., White, J., Shackleford, D. M., Lafuente-Monasterio, M. J., ... 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, Sreekanth ; El Mazouni, Farah ; White, Karen L. ; White, John ; Shackleford, David M. ; Lafuente-Monasterio, Maria Jose ; Manjalanagara, Krishne ; Joseph, Jayan T. ; Garcia-Pérez, Adolfo ; Fernandez, Jorge ; Gamo, Francisco Javier ; Waterson, David ; Burrows, Jeremy N. ; Palmer, Michael J. ; Charman, Susan A. ; Rathod, Pradipsinh K. ; Phillips, Margaret A. / Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity. In: ACS Omega. 2018 ; Vol. 3, No. 8. pp. 9227-9240.
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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 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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Kokkonda, S, El Mazouni, F, White, KL, White, J, Shackleford, DM, Lafuente-Monasterio, MJ, 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

Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity. / Kokkonda, Sreekanth; El Mazouni, Farah; White, Karen L.; White, John; Shackleford, David M.; Lafuente-Monasterio, Maria Jose; Manjalanagara, Krishne; Joseph, Jayan T.; Garcia-Pérez, Adolfo; Fernandez, Jorge; Gamo, Francisco Javier; Waterson, David; Burrows, Jeremy N.; Palmer, Michael J.; Charman, Susan A.; Rathod, Pradipsinh K.; Phillips, Margaret A.

In: ACS Omega, Vol. 3, No. 8, 08.2018, p. 9227-9240.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Isoxazolopyrimidine-Based Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase with Antimalarial Activity

AU - Kokkonda, Sreekanth

AU - El Mazouni, Farah

AU - White, Karen L.

AU - White, John

AU - Shackleford, David M.

AU - Lafuente-Monasterio, Maria Jose

AU - Manjalanagara, Krishne

AU - Joseph, Jayan T.

AU - Garcia-Pérez, Adolfo

AU - Fernandez, Jorge

AU - Gamo, Francisco Javier

AU - Waterson, David

AU - Burrows, Jeremy N.

AU - Palmer, Michael J.

AU - Charman, Susan A.

AU - Rathod, Pradipsinh K.

AU - Phillips, Margaret A.

PY - 2018/8

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N2 - 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.

AB - 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.

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U2 - 10.1021/acsomega.8b01573

DO - 10.1021/acsomega.8b01573

M3 - Article

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EP - 9240

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 8

ER -