Synthesis, molecular docking, molecular dynamic simulation studies, and anti-tubercular activity evaluation of substituted benzimidazole derivatives

Abstract

Abstract Tuberculosis, colloquially referred to as TB, is a highly prevalent bacterial infection that persists as a substantial global health concern. The present article centers its attention on the comprehensive exploration of the synthesis, molecular docking, and molecular dynamic simulation investigations pertaining to substituted benzimidazole derivatives. Additionally, a meticulous assessment of their anti-TB activities is conducted. A series of twelve substituted benzimidazole derivatives (1–12) were successfully synthesized, employing a scaffold consisting of electron-withdrawing and electron-donating groups. The newly synthesized compounds were defined by their FT-IR, 1H-NMR, and Mass spectra. The Microplate Alamar Blue Assay (MABA) was used to evaluate the anti-mycobacterial activity of synthesized compound against Mycobacterium tuberculosis (Mtb). Compounds 7 (MIC = 0.8 g/ml) and 8 (MIC = 0.8 g/ml) demonstrated exceptional potential to inhibit M. tuberculosis compared to the standard (Isoniazid). In addition, the synthesized compounds were docked with the Mtb KasA protein (PDB ID: 6P9K), and the results of molecular docking and molecular dynamic simulation confirmed the experimental results, as compounds 7 and 8 exhibited the highest binding energy of -7.36 and − 7.17 kcal/mol, respectively. Both substances were safe for acute inhalation and cutaneous sensitization. These two compounds have the potential to be potent M. tuberculosis inhibitors.