Design, Synthesis, Characterization and Biological Evaluation of Some Novel Benzimidazole Schiff Base Derivatives as Antitubercular Agents Targeting Glutamine Synthetase 1
Based on the various medicinal chemistry journals Glutamine synthetase1 was selected as the target for the study.
➢ A database of 500 molecules with high prospects of inhibiting the target Glutamine synthetase was carefully chosen by making changes to the known hit molecules, i.e., Benzimidazole chalcones.
➢ The molecules were subjected to toxicity assessment by OSIRIS® property explorer.
➢ In-silico drug likeness properties of the designed molecules were determined by using the MOLINSPIRATION® software.
➢ 500 molecules were docked against the target protein using AutoDock 4 ®.
➢ Five molecules with good docking score [lower binding energy] and interactions were shortlisted and optimized for the synthesis.
➢ Compounds were synthesized with satisfactory yield and labelled as BK-1, BK-2, BK-3, BK-4 and BK-5.
➢ Purity of the synthesized compounds was ensured by repeated recrystallization and the compounds were evaluated by TLC and Melting point.
➢ The characterization of the synthesized compounds was done using Infra-red spectroscopy, Liquid Chromatography-Mass spectrometric methods [LC-MS] and Nuclear Magnetic Resonance [H1 NMR] spectroscopy methods.
➢ The pure compounds were screened for Anti-mycobacterial activity by in-vitro Microplate Alamar Blue Assay [MABA]. MIC of synthesized compound were found in the range of 50μg/ml 3.12 μg/ml.
➢ Acute oral toxicity study was conducted on albino wistar rats and all the compounds were found to be safe and non-toxic.
CONCLUSION:
✓ Novel Benzimidazole chalcone derivatives were found to be capable of inhibiting the target enzyme Glutamine synthetase 1which is essential for the synthesis of mycobacterium cell wall.
✓ The docking score of the designed compound range between -8.56 to -5.87 Kcal/mol.
✓ All the compounds inhibited the Mycobacterium tuberculosis in the range of 3.12μg/ml to 50μg/ml.
✓ The acute toxicity studies revealed that all the compounds are safe and non-toxic.
✓ The MABA test was carried out using H37Rv strain which is non- pathogenic. Hence further studies should be carried out using clinical isolates i.e, Pathogenic strain.
✓ Further structural refinement of the synthesized compounds is expected to yield promising drug candidate against Mycobacterium tuberculosis
