Microwave‐Assisted Synthesis of Novel Symmetric Bis‐1,2,4‐triazolin‐3‐ones as Potent Inhibitors of CYP51: An Antifungal Activity Study

Abstract

AbstractImprovement of antifungal agents is a good solution to beat the drug‐resistance problems. In this context, a series of novel bis‐1,2,4‐triazolin‐3‐ones (5i‐t) were designed and synthesized by microwave irradiation (MWI), a convenient and efficient method. An effort was also made to get these bis‐1,2,4‐triazolin‐3‐ones (5i‐t) by one‐pot three‐component reaction (3CR) using 3‐aryl‐5‐methyl‐1,3,4‐oxadiazol‐2(3H)‐one (2a‐b), formamide and dibromo reagent (4c‐h) under microwave irradiation (MWI). In vitro antifungal activity was carried out against six pathogenic fungi. From the results it was observed that the newly synthesized bis‐1,2,4‐triazolin‐3‐ones (5i‐t) have shown excellent activity against all the tested pathogenic fungi with least MIC values in the range of 0.80 μg/ml to 0.20 μg/ml. Particularly, in comparison with the reference drug Fluconazole and mono‐1,2,4‐triazolin‐3‐ones (3a‐b) some of the bis‐1,2,4‐triazolin‐3‐ones (5i, 5j, 5 m, 5p and 5r) have shown broad spectrum of antifungal activity. Further, the molecular docking study has been performed for all the tested compounds with 14α‐demethylase (CYP51) as target enzyme and this study validated the experimental results. Thus, docking study has culminated in the identification of a new class of potent inhibitors of CYP51. The results provide significant information for the future design of more potent antifungal agents.