Abstract
In this study, two series of benzimidazole hybrids were developed and designed using different strategies. The target compounds were designed through straight chemistry pathways and were screened as possible antimicrobial agents. Twenty new compounds were synthesized, among which compounds 11 and 12 displayed excellent activity against Candida albicans and Cryptococcus neoformans with growth inhibition percentage ranging from 86.42% to 100%. For gaining better insights into the mechanistic ability of the active candidates 11 and 12, their inhibitory activity against lanosterol 14α-demethylase was studied. Results showed IC(50) values of 5.6 and 7.1 μM for 11 and 12, respectively, which were comparable to the reference value of fluconazole (2.3 μM), indicating low drug interaction possibilities. Notably, compound 11 displayed excellent inhibition of biofilm metabolic activity. In addition, their synergistic activity against C. neoformans displayed a 2-fold increase compared with fluconazole. Furthermore, it exhibited sustained antifungal activity with time clearance of over 24 h, which was better than the time clearance of fluconazole (6 h). Moreover, compounds 11 and 12 displayed considerable safety profiles, with no cytotoxicity reported against human embryonic kidney cells or hemolysis of red blood cells. Molecular dynamics simulation (MDS) experiments over 100 ns of compound 11 showed its ability to interact with the HEM binding site as the co-crystallized ligand (fluconazole). Finally, in silico ADMET studies predicted its significant oral bioavailability as antifungal candidates.