Design, Synthesis, Characterization and Biological Evaluation of Some New Heterocyclic Derivatives as Anti-Tubercular Agents

Kalaiselvi, R (2016) Design, Synthesis, Characterization and Biological Evaluation of Some New Heterocyclic Derivatives as Anti-Tubercular Agents. Masters thesis, College of Pharmacy, Madras Medical College, Chennai.


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INTRODUCTION: Tuberculosis is an infectious disease usually caused by the bacteria Mycobacterium tuberculosis. Tuberculosis may infect any part of the body, but most commonly occur in the lungs (known as pulmonary tuberculosis). Extrapulmonary TB occurs when tuberculosis develops outside of the lungs. Extrapulmonary TB may co exist with pulmonary TB. The classic symptoms of active TB are chronic cough with bloodtinged sputum, fever, night sweats and weight loss. Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak or sneeze.(1-2) Active infection occurs more often in people with HIV/AIDS and in those who smoke. One third of the world population is thought to be infected with TB .(1) New infection occur in about 1% of the population each year.(3) In 2014 , there where 9.6 million case of active TB which resulted in 1.5 million deaths .More than 95% of deaths occurred in developing countries (1). About 80% of the people in many Asian and African countries test positive while 5-10 % of people in the United Status population tests positive by the tuberculin test .Tuberculosis has been present in humans since ancient times.AIM:The aim of this project is to discover molecules with potential anti -tubercular activity.OBJECTIVE: Design compounds and docked against a specific crucial target, Methoxy Mycolic acid Synthase 2, which is involved in the cell wall synthesis. The synthesized compounds are expected to act on this enzyme.SUMMARY:Methoxy mycolic acid synthase 2 (1TPY) a critical enzyme for the growth of Mycobacterium tuberculosis was chosen for our study after review of literature. 1.A database of 200 scaffolds with high prospect of inhibiting the target 1TPY were carefully chosen by making changes to the known hit molecules , here the chalcones and thiophene nucleus. 2.Candidate molecules were designed and docked against 1TPY protein using Argus lab 4.1 software. 3.Three 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 assessment by OSIRIS software. The results are color Coded as green color which confirms the drug likeness 5.The molecules were labeled as DKS1, DKS2-1,DKS3 and synthesized with satisfactory yield. 6.Purity of the synthesized compounds was ensured by repeated recrystallization .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 and Mass spectroscopic methods. 8.The final pure compounds were screened for Anti- mycobacterial activity by in vitro method called Microplate Alamar Blue Assay (MABA). CONCLUSION: Our work concludes that our synthesized molecules are effective in inhibiting enzyme Methoxy mycolic acid synthase 2 (1TPY) which is important for the growth of Mycobacterium tuberculosis.  All the three compounds gave Docking score between -7.00 to -10 kcal/mol. Pyrazinamide gave Docking score of -5.6 for 1TPY, Streptomycin gave Docking score of -7.4 for 1TPY and Ciprofloxacin gave Docking score of -5.9 for 1TPY. There is correlation between the core and activities of all the three compounds which were tested and compared with the standard drugs. This goes to prove that Methoxy Mycolic Acid Synthase2 (1TPY) is a critical enzyme for anti-mycobacterial activity. The minimum inhibitory concentration of 3 of the synthesized compounds ranged from 50μg/ml which is compared to that of the known anti-TB agents. Pyrazinamide - 3.125μg/ml, Ciprofloxacin - 3.125μg/ml and Streptomycin - 6.25μg/ml. A further refinement to the structure of the synthesized compounds is expected to yield new outlook to the development of promising molecules against the pathogen Mycobacterium tuberculosis.

Item Type: Thesis (Masters)
Additional Information: Reg.No.261415710
Uncontrolled Keywords: Design ; Synthesis ; Characterization ; Biological Evaluation ; New Heterocyclic Derivatives ; Anti-Tubercular Agents
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 19 Mar 2018 08:44
Last Modified: 21 Mar 2018 07:52

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