# Synthesis, DFT Calculations, In Silico Studies, and Antimicrobial Evaluation of Benzimidazole-Thiadiazole Derivatives

## TL;DR

This study synthesized new benzimidazole-thiadiazole compounds and found some to be effective against fungi and bacteria, with low toxicity.

## Contribution

The paper introduces new benzimidazole-thiadiazole hybrids with potent antimicrobial activity and evaluates their reactivity and binding modes.

## Key findings

- Compounds 5f and 5h showed potent antifungal activity against C. albicans with a MIC of 3.90 μg/mL.
- Compound 5h was found to be chemically more reactive based on HOMO–LUMO analysis.
- Molecular dynamics simulations showed compounds 5f and 5h to be stable in the active site of 14-α demethylase.

## Abstract

In this study, a
series of new benzimidazole-thiadiazole hybrids
were synthesized, and the synthesized compounds were screened for
their antimicrobial activities against eight species of pathogenic
bacteria and three fungal species. Azithromycin, voriconazole, and
fluconazole were used as reference drugs in the mtt assay. Among them,
compounds 5f and 5h showed potent antifungal
activity against C. albicans with a
MIC of 3.90 μg/mL. Further, the results of the antimicrobial
assay for compounds 5a, 5b, 5f, and 5h proved to be potent against E. faecalis (ATCC 2942) on the basis of an acceptable
MIC value of 3.90 μg/mL. The cytotoxic effects of compounds
that are effective as a result of their antimicrobial activity on
healthy mouse fibroblast cells (L929) were evaluated. According to
HOMO–LUMO analysis, compound 5h (with the lower
ΔE = 3.417 eV) is chemically more reactive
than the other molecules, which is compatible with the highest antibacterial
and antifungal activity results. A molecular docking study was performed
to understand their binding modes within the sterol 14-α demethylase
active site and to interpret their promising fungal inhibitory activities.
Molecular dynamics (MD) simulations of the most potent compounds 5f and 5h were found to be quite stable in the
active site of the 14-α demethylase (5TZ1) protein.