2. Academic Validation
  3. Discovery of novel selenium-containing azole derivatives as antifungal agents by exploiting the hydrophobic cleft of CYP51

Discovery of novel selenium-containing azole derivatives as antifungal agents by exploiting the hydrophobic cleft of CYP51

  • Eur J Med Chem. 2022 Aug 28;243:114707. doi: 10.1016/j.ejmech.2022.114707.
Hang Xu 1,  Yan-Hua Mou 2,  Meng-Bi Guo 1,  Rui Zhang 1,  Zhong-Zuo Yan 1,  Ran An 1,  Xin Wang 1,  Xin Su 2,  Zhuang Hou 3,  Chun Guo 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 3 Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: houzhuang8@sina.com.
  • 4 Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: gc_66888@163.com.
PMID: 36057236 DOI: 10.1016/j.ejmech.2022.114707
Abstract

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.

Keywords

Antifungal; CYP51; Diselenides; Selenides.

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