Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 198, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112360
Keywords
Miconazole; Antifungal; Selenium; Bioisosterism; CYP51
Categories
Funding
- National Natural Science Foundation of China [81903463]
- Natural Science Foundation of Liaoning Province [20180540032]
- Career Development Support Plan for Young and Middle-aged Teachers in Shenyang Pharmaceutical University [ZQN2018018]
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Herein, based on the theory of bioisosterism, a series of novel miconazole analogues containing selenium were designed, synthesized and their inhibitory effects on thirteen strains of pathogenic fungi were evaluated. It is especially encouraging that all the novel target compounds displayed significant anti-fungal activities against all tested strains. Furthermore, all the target compounds showed excellent inhibitory effects on fluconazole-resistant fungi. Subsequently, preliminary mechanistic studies indicated that the representative compound A03 had a strong inhibitory effect on C.alb. CYP51. Moreover, the target compounds could prevent the formation of fungi biofilms. Further hemolysis test verified that potential compounds had higher safety than miconazole. In addition, molecular docking study provided the interaction modes between the target compounds and C.alb. CYP51. These results strongly suggested that some target compounds are promising as novel antifungal drugs. (C) 2020 Elsevier Masson SAS. All rights reserved.
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