In vitro biological activity and structural analysis of 2,4-diamino-5-(2′-arylpropargyl)pyrimidine inhibitors of Candida albicans

被引：12
|
作者：
Paulsen, Janet L. [1 ]
Liu, Jieying [1 ]
Bolstad, David B. [1 ]
Smith, Adrienne E. [2 ]
Priestley, Nigel D. [2 ]
Wright, Dennis L. [1 ]
Anderson, Amy C. [1 ]
机构：
[1] Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA
[2] Univ Montana, Dept Chem, Missoula, MT 59812 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 14期
关键词：
Antifolate; Dihydrofolate reductase; Candida albicans; Molecular modeling; DIHYDROFOLATE-REDUCTASE; SELECTIVE INHIBITORS; CRYSTAL-STRUCTURES;
D O I：
10.1016/j.bmc.2009.06.021
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4866 / 4872
页数：7
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