Synthesis, Molecular Docking, Dynamics, Quantum-Chemical Computation, and Antimicrobial Activity Studies of Some New Benzimidazole–Thiadiazole Hybrids

In this study, some
new compounds, which are 2-aminothiadiazole
derivatives linked by a phenyl bridge to the 2-position of the benzimidazole
ring, were designed and synthesized as antimicrobial agents. The structures
of the compounds were elucidated by 1H and 13C NMR spectroscopy, high-resolution mass spectrometry, and elemental
analysis. The antifungal activities of the synthesized compounds were
tested on Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compound 5f is more active against C. albicans and C. glabrata than standard fluconazole
and varicanazole. Compounds were also evaluated for their counteracting
activity against Gram-positive Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas
aeruginosa and Gram-negative Enterococcus
faecalis, Bacillus subtilis, and Staphylococcus aureus. Compounds 5c and 5h had minimum inhibitory concentrations
against E. faecalis close to that of
the standard azithromycin. Molecular docking studies were performed
against Candida species’ 14-α
demethylase enzyme. 5f was the most active compound against Candida species, which gave the highest docking interaction
energy. The stabilities of compounds 5c and 5f with CYP51 were tested using 100 ns molecular dynamics simulations.
According to the theoretical ADME calculations, the profiles of the
compounds are suitable in terms of limiting rules. HOMO–LUMO
analysis showed that 5h is chemically more reactive (represented
with the lower ΔE = 3.432 eV) than the other
molecules, which is compatible with the highest antibacterial activity
result.