Design, synthesis, characterization and biological evaluation of some novel 1, 3, 4 oxadiazole derivatives as anti-tubercular agents targeting L, D transpeptidase 2

Abstract

INTRODUCTION:Tuberculosis is a contagious disease caused by bacteria called Mycobacterium tuberculosis and it is an air borne disease. Tuberculosis generally affects the lungs, but can also affect the other parts of the body. Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or sneeze. People with latent TB do not spread the disease. Active infection occurs more often in people with HIV/AIDS and in those who smoke. Tuberculosis is curable and preventable disease.AIM:The aim of this project is to develop potential antimycobacterial agents.OBJECTIVES: The objective of the project is to design and synthesize some compounds which will act on L, D Transpeptidase 2 and inhibit the cell wall synthesis of M. tuberculosis. SUMMARY: a) L, D-Transpeptidase-2 (3VYP) is a critical enzyme for the cell wall synthesis of Mycobacterium tuberculosis was chosen for study after review of literature. b) Selected molecules were designed and docked against L, D-Transpeptidase-2 (3VYP) using Argus lab® 4.0software. c) Molecules with good Docking score (lower binding energy) and interactions were shortlisted for synthesis. The reaction conditions were optimized. d) The selected molecules were subjected to Toxicity prediction assessments by OSIRIS® software. The results are color coded as green color which predicts the drug likeness. e) Compounds were synthesized by conventional method and labeled as SA, NA, VS1, VS2, VS4 and VS5. f) The purity of the synthesized compounds was ensured by repeated recrystallization. Further the compounds were evaluated by TLC and Melting point determination. g) The characterization of the synthesized compounds was done using Infra-red, Nuclear Magnetic Resonance (H1 NMR &C13NMR) and Mass spectroscopic methods (LC-MS, GC-MS) h) The pure compounds were screened for In-vitro Anti- tubercular activity by Micro plate Alamar Blue Assay (MABA). All compounds showed a significant anti-mycobacterium activity. i) Docking with other critical enzyme was carried out. CONCLUSION:1. Our work concludes that our synthesized molecules are effective in inhibiting the target enzyme L, D-Transpeptidase 2, which is important for the growth of Mycobacterium tuberculosis Cell wall. 2. All the 6 compounds gave Docking score between -8.30 to -9.74kcal/mol. There is correlation between the score and activities of all the 6 compounds which were tested and compared with the standard drugs. 3. Multi target docking was done for different critical enzymes of mycobacterium tuberculosis using Argus lab ®. From the results, the targeted enzyme l,dtranspeptidase 2 score was closer to the other two target ie., diaminopimelate epimerase and glutamine synthase. There was not much significant difference between the other two targeted compounds. 4. The minimum inhibitory concentration of the 6 synthesized compounds against H37RV ranged from 12.5 μg/ml which is better compared to that of the certain known Anti-TB agents. Pyrazinamide- 3.125μg/ml, Ciprofloxacin- 3.125μg/ml and Streptomycin- 6.25μg/ml. Further structural refinement to the structure of the synthesized compounds is expected to yield promising molecules against the pathogen Mycobacterium tuberculosis.