Design Synthesis Characterization and Biological Evaluation of Some Novel Benzothiazole Derivatives as Anti Tubercular Agents Targeting Glutamine Synthetase 1

Bharathi, K (2017) Design Synthesis Characterization and Biological Evaluation of Some Novel Benzothiazole Derivatives as Anti Tubercular Agents Targeting Glutamine Synthetase 1. Masters thesis, College of Pharmacy Madras Medical College, Chennai.


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INTRODUCTION:The most recent World Health Organization (WHO) reports show that there were 9.0 million new tuberculosis (TB) cases and 1.5 million tuberculosis (TB) deaths. Tb is the leading cause of death from an infectious disease worldwide, next to the human immunodeficiency virus (HIV). Co-infection with the HIV fuels the global TB crisis, and successful TB treatment is further complicated and hampered by the existence of multidrug- resistant (MDR) TB and extensively drug resistant (XDR) TB. TUBERCULOSIS is a communicable disease caused by Mycobacterium tuberculosis (MTB), a disease that remains as one of the most alarming health problems worldwide. It is simply spreadable by sneezing, cough and speaking. Predisposing factors for TB include close contact with large populations of people. Humans are the only reservoir for the Mycobacterium tuberculosis. Bedaquiline received U.S. Food and Drug Administration (FDA) approval in late 2011. The safety and effectiveness of these new agents are still uncertain, because they are based on the results of relatively small studies AIM: The aim of this project is to design molecules into potential anti-tubercular activity that is capable of inhibiting cell wall synthesis by inhibiting glutamine synthetase. The designed compounds will be synthesized, characterized and evaluated for activity and toxicity. OBJECTIVE: To design the molecule and docked against a specific crucial target, Glutamine Synthetase I, which is involved in the cell wall biosynthesis and nitrogen metabolism. 1. In-silico prediction of Drug Likeness and Toxicity 2. Laboratory synthesis of the top G score compounds 3. Melting point determination and Thin layer Chromatography 4. Characterization of the synthesized compounds by a) Infrared Spectroscopy b) Nuclear Magnetic Resonance Spectroscopy c) Mass Spectroscopy 5. Determination of in vitro anti tubercular activity of synthesized compounds Summary SUMMARY:1. Glutamine synthetase 1, critical enzyme for the cell wall synthesis of Mycobacterium tuberculosis was chosen after the review of literature. 2. A database of 100 molecules with high probability of inhibiting the target Glutamine Synthetase was chosen by making changes to a known inhibitor scaffold that is aryl substituted benzothiazole nucleus was chosen for the study. 3. In silico drug likeness properties were determined by using Molinspiration® Cheminformatics software based on the Lipinski’s Rule of Five. 4. Docking of the 3D structures of these 100 entities against the 3D structure of Glutamine Synthetase gave an insight about the energetic (molecular docking) by using AUTODOCK® software. 5. Of these 100 structures, only 5 structures which showed minimum binding energy were chosen for synthesis (around -6.6 to -8.0 kcal/mol). They exhibited the better docking score than the standard Anti-TB drugs like Pyrazinamide -4.41kcal/mol by using AUTODOCK ® Software. 6. Toxicity risk assessment prediction was done for all the 5 compounds by OSIRIS® property explorer which is available online. The results are colour coded as green colour, which predict the drug likeness. 7. The purity of the synthesized compounds were confirmed by TLC and melting point and then characterized by IR, 1H NMR, GC-MS and LC-MS. 8. The pure compounds were screened for in vitro Antitubercular activity by Microplate Alamar Blue Assay method. 9. The synthesized compounds showed sensitivity (Minimum Inhibitory Concentration) in the range 12.5-6.25µg/ml. The standard drugs Pyrazinamide, Ciprofloxacin and Streptomycin exhibited antimycobacterial activity at 3.125µg/ml, 3.125µg/ml and 6.25µg/ml concentration respectively. This indicates that the synthesized compounds are as active as the standard drugs. 10. The synthesized compounds showed better docking score than Pyrazinamide. However, all of them are less active than Pyrazinamide. 11. The synthesized compounds have related docking score around 6.5-8.2 Kcal/mol against various target. Therefore, they are capable of inhibiting Decaprenylphosporyl β-d-Ribose 2-Epimerase, Cyclopropane Mycolic Acid Synthase 2 and Methoxy Mycolic acid Synthetase 2, which is also had the functional importance in the Mycobacterium tuberculosis. CONCLUSION:It is concluded that the synthesized compounds might effectively inhibit the chosen target Glutamine Synthetase I which is essential for the Mycobacterial Tuberculosis. Further structural modifications of the synthesized compounds will aid in the development of potential molecule against the tuberculosis pathogen.

Item Type: Thesis (Masters)
Additional Information: Reg.No.261515701
Uncontrolled Keywords: Design ; Synthesis Characterization ; Biological Evaluation ; Some Novel Benzothiazole Derivatives ; Anti Tubercular Agents ; Targeting Glutamine Synthetase 1
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 19 Mar 2018 09:11
Last Modified: 19 Mar 2018 09:11

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