2-(苯并[b]噻吩-2-基)-4-苯基-4,5-二氢恶唑衍生物作为广谱抗真菌剂的设计、合成及生物活性评价
Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents.
作者信息
Zhao Liyu, Sun Yin, Yin Wenbo, Tian Linfeng, Sun Nannan, Zheng Yang, Zhang Chu, Zhao Shizhen, Su Xin, Zhao Dongmei, Cheng Maosheng
机构信息
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
Key Laboratory of Receptor-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, 475004, China.
出版信息
Eur J Med Chem. 2022 Jan 15;228:113987. doi: 10.1016/j.ejmech.2021.113987. Epub 2021 Nov 12.
To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03-0.5 μg/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25-2 μg/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro, with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study.
为了发现具有广谱和稳定代谢的抗真菌化合物，设计并合成了一系列2-(苯并[b]噻吩-2-基)-4-苯基-4,5-二氢恶唑衍生物。化合物A30 - A34对白色念珠菌表现出优异的广谱抗真菌活性，其最低抑菌浓度（MIC）值在0.03 - 0.5μg/mL范围内，对新型隐球菌和烟曲霉的MIC值在0.25 - 2μg/mL范围内。此外，化合物A31和A33在体外人肝微粒体中显示出高代谢稳定性，半衰期分别为80.5分钟和69.4分钟。而且，化合物A31和A33对CYP3A4和CYP2D6显示出微弱或几乎没有抑制作用。在SD大鼠中的药代动力学评价表明，化合物A31具有合适的药代动力学性质，值得进一步研究。
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