Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum

Margaret A. Phillips; Ramesh Gujjar; Nicholas A. Malmquist; John White; Farah El Mazouni; Jeffrey Baldwin; Pradipsinh K. Rathod

doi:10.1021/jm8001026

Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum

Margaret A. Phillips, Ramesh Gujjar, Nicholas A. Malmquist, John White, Farah El Mazouni, Jeffrey Baldwin, Pradipsinh K. Rathod

Research output: Contribution to journal › Article › peer-review

187 Scopus citations

Abstract

A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor that is potent (K_I = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC ₅₀ = 79 nM).

Original language	English (US)
Pages (from-to)	3649-3653
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	51
Issue number	12
DOIs	https://doi.org/10.1021/jm8001026
State	Published - Jun 26 2008

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum",

abstract = "A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC 50 = 79 nM).",

author = "Phillips, {Margaret A.} and Ramesh Gujjar and Malmquist, {Nicholas A.} and John White and {El Mazouni}, Farah and Jeffrey Baldwin and Rathod, {Pradipsinh K.}",

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doi = "10.1021/jm8001026",

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T1 - Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum

AU - Phillips, Margaret A.

AU - Gujjar, Ramesh

AU - Malmquist, Nicholas A.

AU - White, John

AU - El Mazouni, Farah

AU - Baldwin, Jeffrey

AU - Rathod, Pradipsinh K.

PY - 2008/6/26

Y1 - 2008/6/26

N2 - A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC 50 = 79 nM).

AB - A Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitor that is potent (KI = 15 nM) and species-selective (>5000-fold over the human enzyme) was identified by high-throughput screening. The substituted triazolopyrimidine and its structural analogues were produced by an inexpensive three-step synthesis, and the series showed good association between PfDHODH inhibition and parasite toxicity. This study has identified the first nanomolar PfDHODH inhibitor with potent antimalarial activity in whole cells (EC 50 = 79 nM).

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Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum

Abstract

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