新型三唑类化合物的设计、合成及广谱抗真菌活性的生物学研究。
Design, synthesis and biological studies of novel triazoles with potent and broad-spectrum antifungal activity.
机构信息
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, Shanghai, China.
Department of Pharmacy, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
出版信息
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2244696. doi: 10.1080/14756366.2023.2244696.
A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against SC5314, 22-21, 537 and 22-20 with MIC values in the range of ≤0.125 µg/mL-4.0 µg/mL. In addition, compounds , , , and showed inhibitory activities against fluconazole-resistant and . Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that , , and interfered with the ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of and with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents.
设计并合成了一系列含有芳基-丙酰胺侧链的新型三唑衍生物。抗真菌活性研究表明，大多数化合物抑制了六种人体致病真菌的生长。特别是，含有苯丙酰胺的部分化合物对 SC5314、22-21、537 和 22-20 具有出色的广谱抗真菌活性，MIC 值在≤0.125 μg/mL-4.0 μg/mL 范围内。此外，化合物 、 、 、 和 对氟康唑耐药的 和 也表现出抑制活性。初步的构效关系（SAR）也进行了总结。此外，GC-MS 分析表明， 、 和 通过抑制 Cyp51 干扰麦角固醇生物合成途径。分子对接研究阐明了 与 Cyp51 的结合模式。这些化合物具有低溶血活性和有利的 ADME/T 特性，有望开发新型抗真菌药物。
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