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Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.

Abstract：

:Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Heikkilä T,Ramsey C,Davies M,Galtier C,Stead AM,Johnson AP,Fishwick CW,Boa AN,McConkey GA

doi

10.1021/jm060687j

subject

Has Abstract

pub_date

2007-01-25 00:00:00

pages

186-91

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

50

pub_type

杂志文章

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