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§ and Pradipsinh K. Rathod*#
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, Texas 75390-9041, and Department of Chemistry and Global Health, University of Washington, Seattle, Washington 98195
J. Med. Chem., 2008, 51 (12), pp 3649–3653
DOI: 10.1021/jm8001026
Publication Date (Web): June 4, 2008
Copyright © 2008 American Chemical Society
* To whom correspondence should be addressed. For M.A.P.: phone, (214) 645-6164 ; fax, (214) 645-6166; e-mail, margaret.phillips@UTSouthwestern.edu. For P.K.R.: phone, (206) 221-6069 ; fax, (206) 685-8665; e-mail, rathod@chem.washington.edu.
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§

University of Texas Southwestern Medical Center at Dallas.

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#

University of Washington.

Abstract

Abstract Image

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 (EC50 = 79 nM).

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History

  • Published In Issue June 26, 2008
  • Article ASAPJune 04, 2008
  • Received: January 31, 2008

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