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Design, synthesis, and biological evaluation of Plasmodium falciparum lactate dehydrogenase inhibitors.

Abstract：

:Plasmodium falciparum lactate dehydrogenase (pfLDH) is a key enzyme for energy generation of malarial parasites and is a potential antimalarial chemotherapeutic target. It is known that the oxamate moiety, a pyruvate analog, alone shows higher inhibition against pfLDH than human LDHs, suggesting that it can be used for the development of selective inhibitors. Oxamic acid derivatives were designed and synthesized. Derivatives 5 and 7 demonstrated activities against pfLDH with IC50 values of 3.13 and 1.75 muM, respectively, and have 59- and 7-fold selectivity over mammalian LDH, respectively. They also have micromolar range activities against Plasmodium falciparum malate dehydrogenase (pfMDH), which may fill the role of pfLDH when the activity of pfLDH is reduced. Thus, certain members of these oxamic acid derivatives may have dual inhibitory activities against both pfLDH and pfMDH. It is presumed that dual LDH/MDH inhibitors would have enhanced potential as antimalarial drugs.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Choi SR,Pradhan A,Hammond NL,Chittiboyina AG,Tekwani BL,Avery MA

doi

10.1021/jm070336k

subject

Has Abstract

pub_date

2007-08-09 00:00:00

pages

3841-50

issue

16

eissn

0022-2623

issn

1520-4804

journal_volume

50

pub_type

杂志文章

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