Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel Tribromo-substituted Imidazole Analogs

• It has been demonstrated that compounds with imidazole nucleus can be good antimicrobial and anti-mycobacterial compounds by performing in vitro investigations of the synthesized imidazole derivatives . • Using the B3LYP level of theory, DFT simulations were performed on the most active analogs of the series, to investigate the molecular geometry and other molecular properties. • The DFT-optimized molecules were docked with two proteins one of which is involved in the synthesis of the bacterial and fungal cell wall building block and the other is the protein structure of the Mycobacterium tuberculosis , using Autodock tools, and their results were compared to the reference drugs- streptomycin , metronidazole , fluconazole , and, pyrazinamide , used in the study. • The docked complexes were used to determine the binding free energies (ΔG bind ), of the most active analogs 3g and 4i . • The research opens new horizons to investigate halo-imidazoles as antimicrobials and anti-mycobacterials. With the increasing rate of antimicrobial resistance, there is an urgent demand of developing newer antimicrobial agents. In the present study we report a novel series of eighteen 1-(aryl)-2-(2,4,5-tribromo-1H-imidazol-1-yl)ethan-1-ones, which were synthesized and their spectral characterization was performed. The in-vitro studies of the compounds were carried out. Molecular modeling studies were performed on the most promising compound. The results obtained would help develop new compounds that may have broad-spectrum therapeutic effects. The compounds were synthesized by reacting the corresponding bromo-imidazoles with substituted phenacyl bromides. The predictive ADME studies, MM-GBSA studies, and In-vitro studies were carried out for all the compounds. Binding mode analysis of the most active compounds was carried out. DFT investigations were also performed. All the synthesized compounds were found to be active against the different strains of microorganisms used in the in-vitro analysis. Binding mode analysis of the most active compounds were carried out in the active site of glucosamine-6-phosphate synthase (2VF5) and crystal structure of Mycobacterium tuberculosis InhA inhibited by PT70 (2X22). With the increasing global challenge of multi-drug resistance and the urgent need for new antimicrobial agents, these compounds show promising potential to meet emerging therapeutic demands in treating infectious diseases.