Design, Synthesis, Characterization and Biological Evaluation of Some Novel Anti Tubercular Agents Targeting L, D-Transpeptidase-2

Mala, S (2016) Design, Synthesis, Characterization and Biological Evaluation of Some Novel Anti Tubercular Agents Targeting L, D-Transpeptidase-2. Masters thesis, College of Pharmacy, Madras Medical College, Chennai.


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INTRODUCTION:Tuberculosis or TB is the most common infectious disease. In the past Tuberculosis also called as phthisis or phthisis pulmonalis. TB is second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent.(1) In addition, the prevalence of drug-resistant TB is also increasing worldwide. Co-infection with HIV has been an important factor in the emergence and spread of resistance. (2) New TB treatments are being developed and new vaccines are currently under investigation. (3) TB is a major global health threat, and there is need to improve the existing treatment regimen to control the spread of TB. Tuberculosis is an airborne disease. It is spread from person to person through the air (vehicle).Tuberculosis is most often affect the lungs.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:L, 1. D-Transpeptidase-2 (4GSU), a critical enzyme for the cell wall synthesis of Mycobacterium tuberculosis was chosen for study after review of literature. 2. Candidate molecules were designed and docked against 4GSU protein using Argus lab 4.0software. 3. Molecules with good Docking score (lower binding energy) and interactions were shortlisted for synthesis. The reaction conditions were optimized. 4. The selected molecules were subjected to Toxicity prediction assessments by OSIRIS® software. The results are color coded as green color which confirms the drug likeness. 5. Compounds were synthesized by conventional method and labeled as 9-F,9-DF,9-V,9-S,9-P,9-DM,9-PD,and 9-CN. 6. Purity of the synthesized compounds was ensured by repeated recrystallization. Further the compounds were evaluated by TLC and Melting point determination. 7. The characterization of the synthesized compounds was done using Infra-red, Nuclear Magnetic Resonance (H1 NMR) and Mass spectroscopic methods (LC-MS, GC-MS) 8. 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. 9. The synthesized compounds were active at 1.6 - 50μg/ml, which were comparable into the known anti-TB drugs: Pyrazinamide - 3.125μg/ml, Ciprofloxacin - 3.125μg/ml and Streptomycin - 6.25μg/ml CONCLUSION: 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. All the 8 compounds gave Docking score between -8.20 to - 11.42kcal/mol. Pyrazinamide gave Docking score of -5.6 for 4GSU, Streptomycin gave Docking score of -7.4 for 4GSU and Ciprofloxacin gave Docking score of -5.9 for 4GSU. There is correlation between the score and activities of all the 8 compounds which were tested and compared with the standard drugs. This goes to prove that 4GSU is a critical enzyme for anti-mycobacterial activity. The minimum inhibitory concentration of the 8 synthesized compounds against H37RV ranged from 12.5 to 1.5.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.

Item Type: Thesis (Masters)
Additional Information: Reg. No. 261415713
Uncontrolled Keywords: Design ; Synthesis ; Characterization ; Biological Evaluation ; Novel Anti Tubercular Agents ; Targeting L ; D-Transpeptidase-2.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 16 Mar 2018 10:06
Last Modified: 21 Mar 2018 11:51

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