Wu Xudong, Zhang Jiachen, Liu Rongrong, Sun Yixiang, Gao Zixuan, Zhang Guoqi, Luo Zirui, Li Kejian, Qin Qiaohua, Liu Nian, Zhang Haoyu, Su Xin, Zhao Dongmei, Cheng Maosheng
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
The School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Bioorg Chem. 2024 Dec;153:107785. doi: 10.1016/j.bioorg.2024.107785. Epub 2024 Sep 6.
Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using Iodiconazole as the lead compound. Among them, compound 19g is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus, with a MIC value of 0.0625 μg/mL. In addition, compounds 19e, 19f, 19g, 19h, 19i and 19k exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound 19g had optimal in vitro antifungal activity, we selected 19g for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound 19g on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound 19g on the filamentation of Candida albicans and determined the mechanism of action by sterol composition analysis.
侵袭性真菌感染具有较高的发病率和死亡率，已成为对人类健康最严重的威胁之一。在本研究中，以碘康唑为先导化合物，通过对先导化合物进行结构修饰，获得了一系列具有苯并噻吩骨架的三唑类抗真菌衍生物。其中，化合物19g是一种具有4-氯-2-氟苯并噻吩骨架的三唑类抗真菌化合物，对白色念珠菌、新型隐球菌和曲霉菌显示出最佳的抗真菌活性，MIC值为0.0625μg/mL。此外，化合物19e、19f、19g、19h、19i和19k对氟康唑耐药菌株表现出不同程度的抑制活性，MIC值范围为0.0625μg/mL至32μg/mL。由于化合物19g具有最佳的体外抗真菌活性，我们选择19g进行人肝微粒体稳定性和CYP酶抑制试验，并进一步评估化合物19g对人正常细胞和癌细胞的抑制活性。最后，我们验证了化合物19g对白色念珠菌丝状化的抑制作用，并通过甾醇成分分析确定了其作用机制。
