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

•Compounds 4a and 4b are the most effective derivatives.•Molecular docking studies of compounds were performed at the active site of 14-alpha demethylase and estimated ADME profiles were calculated.•Calculated values of the electrophilicity index indicate the ability of 4b and 4c to behave as stronger electrophiles in chemical reactions.•MD simulation for 100 ns these four protein-ligand complexes which revealed mean RMSD values of CYP51-4a, CYP51-4b, CYP51-4c, & CYP51-4d are 0.22, 0.28, 0.26, and 0.23 nm, respectively. In this study, a series of new 3-((5-(4-(5-substitue-1H-benz[d]imidazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)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 1H NMR, 13C NMR, and MS spectral data analysis results. The results demonstrated that compounds 4a (MIC50=0,78 µg/mL) and 4b (MIC50=0,78 µg/mL) possessed better inhibitory activity against C. albicans than ketoconazole (MIC50=1,56 µg/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.