Design, synthesis and antimycobacterial evaluation of benzimidazole-thiazolylhydrazone derivatives: In silico molecular docking studies, DFT analysis and ADMET predictions

Tuberculosis (TB) remains a significant global health challenge, with 10 million new cases and 1 million deaths annually. The limited availability of anti-TB drugs, prolonged treatment regimens, and drug resistance underscores the urgent need for new therapeutic agents. Leveraging the pharmacological potential of benzimidazole and thiazolylhydrazone scaffolds, we designed and synthesized a series of novel benzimidazole-thiazolylhydrazone derivatives. These compounds were prepared via reactions of phenacyl bromides with thiosemicarbazide and benzimidazole-containing arylaldehydes in ethanol with catalytic acetic acid. In vitro testing against Mycobacterium tuberculosis (H37Rv) revealed notable activity for 4-fluorophenyl (4b) and 4-bromophenyl (4d) derivatives, with MIC values of 3.125 μg/mL and 6.25 μg/mL, respectively. Molecular docking suggested compound 4b targets DprE1, crucial in mycobacterial cell wall synthesis, with a binding energy of −10.9 kcal/mol. In silico ADME analysis confirmed drug-likeness, and TOPKAT studies indicated non-carcinogenicity. These results position compound 4b as a promising lead for further TB drug development.