Synthesis and Evaluation of α-Thymidine Analogues as Novel Antimalarials

被引：35

作者：

Cui, Huaqing ^{[1
,2
]}

Carrero-Lerida, Juana ^{[2
]}

Silva, Ana P. G. ^{[3
]}

Whittingham, Jean L. ^{[3
]}

Brannigan, James A. ^{[3
]}

Ruiz-Perez, Luis M. ^{[2
]}

Read, Kevin D. ^{[1
]}

Wilson, Keith S. ^{[3
]}

Gonzalez-Pacanowska, Dolores ^{[2
]}

Gilbert, Ian H. ^{[1
]}

机构：

[1] Univ Dundee, Sir James Black Ctr, Coll Life Sci, Div Biol Chem & Drug Discovery, Dundee DD1 5EH, Scotland

[2] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain

[3] Univ York, Dept Chem, Struct Biol Lab, York YO10 5DD, N Yorkshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 24期

基金：

英国惠康基金;

关键词：

MYCOBACTERIUM-TUBERCULOSIS; EFFICIENT PHOSPHORYLATION; MONOPHOSPHATE KINASE; NUCLEOSIDE ANALOGS; STRUCTURAL BASIS; BETA-THYMIDINE; HUMAN MALARIA; INHIBITORS; PURINE;

D O I：

10.1021/jm301328h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-alpha-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-alpha- and beta-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-alpha-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC50 = 28 nM; CC50 = 29 mu M).

引用

页码：10948 / 10957

页数：10

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