Design and synthesis of pyridine-substituted itraconazole analogues with improved antifungal activities, water solubility and bioavailability |
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Authors: | Yu LiuZining Liu Xufeng CaoXin Liu Huili HeYushe Yang |
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Institution: | State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China |
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Abstract: | To improve antifungal activities, water solubility and bioavailability, a series of novel analogues of itraconazole-containing pyridine rings were designed and synthesized. Their antifungal activities were evaluated in vitro against six clinically important fungi by measuring the minimal inhibitory concentrations (MICs). Most of the compounds showed more potent antifungal activities than that of itraconazole. In particular, the analogues 30d, 30c, 31c, and 36d exhibited much higher solubility and bioavailability than that of itraconazole. The bioavailability of 36d (42.2%) was five times higher than that of itraconazole (8%) and was negative for genetic toxicology in the Ames test. |
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Keywords: | Itraconazole analogues Synthesis Antifungal Bioavailability |
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