Design, Molecular Docking and ADMET Analysis of Mannich-Base Substituted Benzimidazole Derivatives as Potential Antimicrobial Agents

Background

The growing incidence of antimicrobial resistance demands the development of new therapeutic agents with improved safety and efficacy. Benzimidazole derivatives are considered promising pharmacophores due to their broad biological activities, particularly their potential to inhibit DNA gyrase.

Objectives

This study aims to design and computationally evaluate novel Mannich base-substituted benzimidazole derivatives as potential antimicrobial agents targeting DNA gyrase.

Materials and Methods

Ten benzimidazole derivatives are designed and optimized using various in silico approaches. Molecular docking is performed to analyze their binding affinity toward DNA gyrase. Physicochemical properties, bioactivity scores, toxicity risks, and ADMET parameters are predicted using Molinspiration, OSIRIS, and SwissADME tools.

Results

Docking results demonstrate favorable interactions of the designed molecules within the active site of DNA gyrase. Among them, compound 2ASA exhibits the highest binding affinity (-9.06 kcal/mol), surpassing the reference drug ciprofloxacin. All compounds satisfy Lipinski’s rule of five, indicating good oral drug-likeness. Bioactivity predictions suggest enzyme inhibitory potential, and most derivatives display high gastrointestinal absorption with minimal predicted toxicity.

Conclusion

These findings identify compound 2ASA as a promising lead molecule and support further experimental validation of Mannich base-substituted benzimidazole derivatives for antimicrobial drug development.