Institute of Chemical Biology and Drug Discovery , Stony Brook University , Stony Brook , New York 11794-3400 , United States.
Department of Chemistry , Stony Brook University , Stony Brook , New York 11794-3400 , United States.
J Med Chem. 2019 Sep 12;62(17):8249-8273. doi: 10.1021/acs.jmedchem.9b01004. Epub 2019 Aug 16.
Recently, the fungal sphingolipid glucosylceramide (GlcCer) synthesis has emerged as a highly promising new target for drug discovery of next-generation antifungal agents, and we found two aromatic acylhydrazones as effective inhibitors of GlcCer synthesis based on HTP screening. In the present work, we have designed libraries of new aromatic acylhydrazones, evaluated their antifungal activities (MIC and time-kill profile) against , and performed an extensive SAR study, which led to the identification of five promising lead compounds, exhibiting excellent fungicidal activities with very large selectivity index. Moreover, two compounds demonstrated broad spectrum antifungal activity against six other clinically relevant fungal strains. These five lead compounds were examined for their synergism/cooperativity with five clinical drugs against seven fungal strains, and very encouraging results were obtained; e.g., the combination of all five lead compounds with voriconazole exhibited either synergistic or additive effect to all seven fungal strains.
最近，真菌鞘氨醇葡萄糖苷（GlcCer）的合成已成为新一代抗真菌药物发现的极具前景的新靶点，我们基于高通量筛选（HTP）发现了两种芳香酰腙作为 GlcCer 合成的有效抑制剂。在本工作中，我们设计了一系列新型芳香酰腙库，评估了它们对 的抗真菌活性（MIC 和时间杀伤曲线），并进行了广泛的 SAR 研究，确定了 5 种有前途的先导化合物，具有极好的杀菌活性和非常大的选择性指数。此外，两种化合物对其他 6 种临床相关真菌株表现出广谱抗真菌活性。我们还研究了这 5 种先导化合物与 5 种临床药物联合使用对 7 种真菌株的协同/合作作用，结果非常令人鼓舞；例如，所有 5 种先导化合物与伏立康唑联合使用对所有 7 种真菌株均表现出协同或相加作用。
