Design, Synthesis,Characterization and Biological Evaluation of Some Novel Benzimidazole Derivatives as Anti-Tubercular Agents Targeting Inha (Enoyl Acyl Carrier Protein Reductase) Enzyme

InhA (Enoyl acyl carrier protein reductase), a critical enzyme for the cell wall synthesis of Mycobacterium tuberculosis was chosen for study after review of literature. Candidate molecules were designed and docked against 2h9i protein using Autodock Tools® 1.5.6 software. Molecules with good Docking score (lower binding energy) and favourable interactions were checked for druglikeness and toxicity. The selected molecules were subjected to Toxicity prediction assessment by OSIRIS® software Compounds with good activity, druglikeness and absence of significant toxicity were shortlisted for synthesis. Compounds were synthesized by conventional method and labelled as SC, SJ, SM, SN, SE Purity of the synthesized compounds was ensured by repeated recrystallization with Methanol. Further the compounds were evaluated by TLC and Melting point were determined. The characterization of the synthesized compounds was done using Infra-Red (IR), Nuclear Magnetic Resonance Spectroscopy(1H NMR) and Mass spectrometry (LC-MS). The pure compounds were screened for In-vitro Anti- tubercular activity by Micro plate Alamar Blue Assay (MABA). All compounds showed good anti-mycobacterial activity. The synthesized compounds were active at concentrations of 1.6-25.0μg/ml, which were comparable to the known anti-TB drugs: Pyrazinamide-3.125μg/ml, Ciprofloxacin - 3.125μg/ml and Streptomycin - 6.25μg/ml. CONCLUSION The work concludes that the synthesized molecules are effective in inhibiting the target enzyme InhA , which is important for the growth of Mycobacterium tuberculosis cell wall. All the five compounds gave Docking score between -6.8 to -8.38 kcal/mol. There is a correlation between the docking score and actual activities of all the compounds which were tested and compared with the standard drugs. This goes to prove that 2h9i is a critical enzyme for anti-mycobacterial activity. Further structural refinement to the structure of the synthesized compounds is expected to yield promising molecules against the pathogen Mycobacterium tuberculosis