Synthesis, molecular modeling, quantum mechanical calculations and ADME estimation studies of benzimidazole-oxadiazole derivatives as potent antifungal agents

In this study, a series of new 3-((5-(4-(5-substitue-1 H -benz[ d ]imidazol-2-yl)phenyl)-1,3,4-oxadiazol-2yl)thio)-1-phenyl propane-1-on ( 4a-4d ) derivatives has been designed and synthesized as probable antifungal agents. The final compounds were screened for antifungal activity against Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 22019) and Candida albicans (ATCC 24433) by employing the broth micro-dilution method. All the new compounds' structures were elucidated by 1 H NMR, 13 C NMR, and MS spectral data analysis results. The results demonstrated that compounds 4a (MIC 50 = 0,78 mu g/mL) and 4b (MIC 50 = 0,78 mu g/mL) possessed better inhibitory activity against C. albicans than ketoconazole (MIC 50 = 1,56 mu g/mL). Molecular docking studies of compounds were performed at the active site of 14-alpha demethylase and estimated ADME profiles were calculated. Furthermore, 100 ns simulations were carried out of CYP51-4a, CYP51-4b, CYP51-4c, & CYP51-4d, protein-ligand complexes which revealed mean RMSD values are 0.22, 0.28, 0.26, and 0.23 nm, respectively. The simulation result shows lead compounds bound tightly within the cavity of the CYP51 target protein and thus having conformational stability. The simulation and MM/PBSA results reveal that all ligand-protein complexes are stable and have stable interactions till 100 ns simulation time. Thus, these synthesized lead compounds can be further analyzed for in vitro, in vivo experimental validation as antifungal candidates. (c) 2021 Elsevier B.V. All rights reserved.

Automated summary

A series of new compounds were designed and synthesized as potential antifungal agents, with compounds 4a and 4b showing better inhibitory activity against Candida albicans than ketoconazole. Molecular docking studies and 100 ns simulations revealed stable interactions between the lead compounds and target proteins, supporting their further analysis as antifungal candidates.