Department of Pharmaceutical Sciences, University of Connecticut , 69 N. Eagleville Road, Storrs, Connecticut 06269, United States.
J Med Chem. 2014 Mar 27;57(6):2643-56. doi: 10.1021/jm401916j. Epub 2014 Mar 6.
Species of Candida, primarily C. albicans and with increasing prevalence, C. glabrata, are responsible for the majority of fungal bloodstream infections that cause morbidity, especially among immune compromised patients. While the development of new antifungal agents that target the essential enzyme, dihydrofolate reductase (DHFR), in both Candida species would be ideal, previous attempts have resulted in antifolates that exhibit inconsistencies between enzyme inhibition and antifungal properties. In this article, we describe the evaluation of pairs of propargyl-linked antifolates that possess similar physicochemical properties but different shapes. All of these compounds are effective at inhibiting the fungal enzymes and the growth of C. glabrata; however, the inhibition of the growth of C. albicans is shape-dependent with extended para-linked compounds proving more effective than compact, meta-linked compounds. Using crystal structures of DHFR from C. albicans and C. glabrata bound to lead compounds, 13 new para-linked compounds designed to inhibit both species were synthesized. Eight of these compounds potently inhibit the growth of both fungal species with three compounds displaying dual MIC values less than 1 μg/mL. Analysis of the active compounds shows that shape and distribution of polar functionality is critical in achieving dual antifungal activity.
念珠菌属的物种，主要是白色念珠菌和日益流行的光滑念珠菌，是引起发病率的大多数真菌性血流感染的原因，特别是在免疫功能低下的患者中。虽然开发针对白色念珠菌和光滑念珠菌中必需酶二氢叶酸还原酶（DHFR）的新型抗真菌药物是理想的，但以前的尝试导致了抗叶酸药物在酶抑制和抗真菌特性之间存在不一致。在本文中，我们描述了对具有相似物理化学性质但形状不同的炔丙基连接的抗叶酸的评估。所有这些化合物都能有效抑制真菌酶和光滑念珠菌的生长；然而，白色念珠菌生长的抑制取决于形状，延长的对位连接化合物比紧凑的间位连接化合物更有效。使用与先导化合物结合的白色念珠菌和光滑念珠菌的 DHFR 晶体结构，合成了 13 种新的设计用于抑制两种真菌的对位连接化合物。其中 8 种化合物能强烈抑制两种真菌的生长，其中 3 种化合物的双重 MIC 值小于 1 μg/ml。对活性化合物的分析表明，形状和极性功能分布在实现双重抗真菌活性方面至关重要。
