Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Eur J Med Chem. 2022 Dec 5;243:114707. doi: 10.1016/j.ejmech.2022.114707. Epub 2022 Aug 28.
Herein, we report the design, synthesis and evaluation of a novel series of diselenide and selenide derivatives as potent antifungal agents by exploiting the hydrophobic cleft of CYP51. Among all synthesized compounds, the most potent compound B01 with low cytotoxic and hemolysis effect exhibited excellent activity against C.alb., C.gla., C.par. and C.kru., as well as selected fluconazole-resistant strains. Moreover, compound B01 could reduce the biofilm formation of the FCZ-resistant C.alb. Subsequently, metabolic stability assays using liver microsomes demonstrated that compound B01 showed good profiles of metabolic stability. With superior pharmacological profile, compound B01 was advanced into in vivo bioactivity evaluation. In a murine model of systemic C.alb. infection, compound B01 significantly reduced fungal load of kidneys. Furthermore, compound B01 revealed relatively low acute toxicity and subacute toxicity in mice. In addition, docking study performed into C.alb. CYP51, showed the binding mode between C.alb. CYP51 and compound B01. Collectively, diselenides compound B01 can be further developed for the potential treatment of invasive fungal infections.
在这里，我们通过利用 CYP51 的疏水裂缝，设计、合成和评估了一系列新型二硒化物和硒化物衍生物，作为有效的抗真菌剂。在所合成的所有化合物中，具有低细胞毒性和溶血作用的最有效化合物 B01 对 C.alb.、C.gla.、C.par. 和 C.kru. 以及选定的氟康唑耐药株表现出优异的活性。此外，化合物 B01 可以减少 FCZ 耐药 C.alb 的生物膜形成。随后，使用肝微粒体进行的代谢稳定性测定表明，化合物 B01 表现出良好的代谢稳定性特征。具有优越的药理学特征，化合物 B01 被推进到体内生物活性评价。在系统性 C.alb. 感染的小鼠模型中，化合物 B01 显著降低了肾脏中的真菌负荷。此外，化合物 B01 在小鼠中显示出相对较低的急性毒性和亚急性毒性。此外，在 C.alb. CYP51 中进行的对接研究表明了 C.alb. CYP51 与化合物 B01 之间的结合模式。总之，二硒化物化合物 B01 可以进一步开发用于治疗侵袭性真菌感染。
