Design, Synthesis, Characterization and Biological Evaluation of Some Novel Anti Tubercular Agents Targeting L, D-Transpeptidase-2
2016
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.
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