Design, Synthesis and Biological Evaluation of Novel Saccharin Derivatives as Anti-Tubercular Agents Targeting Glutamine Synthetase

Anguraj, M (2021) Design, Synthesis and Biological Evaluation of Novel Saccharin Derivatives as Anti-Tubercular Agents Targeting Glutamine Synthetase. Masters thesis, College of Pharmacy, Madras Medical College, Chennai.


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Glutamine synthetase I is a vital enzyme present in the cell wall of Mycobacterium tuberculosis H37Rv. It belongs to the Ligase family was chosen after the review of literature. • A database of 500 molecules with high prospects of inhibiting the target Glutamine synthetase I were carefully chosen by making changes to the known hit molecules, here the saccharin nucleus was chosen. • The designed molecules were docked against the target chosen using AutoDock 4® TOOLS 1.5.6 software. • Seven molecules (AMA-1, AMA-2, AMA-3, AMA-4, AMA-5, AMA-6 and AMA-7) with good docking score [lower binding energy] and interactions were shortlisted for synthesis. • The selected molecules were subjected to toxicity prediction assessment by OSIRIS® property explorer developed by Acetilon Pharmaceuticals limited which is available online. The results are color coded as green color which predicts the drug likeness and possibly better activity. • The reaction condition were optimized, synthesized and labelled as BOB, CIN, NIB, OHB, PHB. • The characterization of the synthesized compounds was done using TLC, Melting point Infra-red, Mass spectrometric methods [LC-MS] and Nuclear Magnetic Resonance [H1 NMR] spectroscopy methods. • All the Synthesized compounds exhibited molecular ion peak (M+) of varying intensities. • The final pure compounds were screened for Anti-mycobacterial activity by in vitro method called Microplate Alamar Blue Assay [MABA]. • The synthesized compounds showed sensitivity [Minimum inhibitory concentration] at 12.5mcg/ml. The standard drugs Isoniazide, Ethambutol, Pyrazinamide, rifampicin and and Streptomycin exhibited anti-mycobacterial activity at 1.6mcg/ml, 1.6mcg/ml, 3.125mcg/ml, 0.8mcg/ml and 0.8mcg/ml concentrations respectively. This indicates that the synthesized compounds are as Potent as the standard drugs. • Based on the MABA report, Acute Oral Toxicity study were performed and observed that the administration of the synthesized molecules by oral route upto 2000mg/kg/b.w is safe. CONCLUSION: The current research work concludes that, • Glutamine Synthetase I is one of the critical enzymes essential for the growth and survival of Mycobacterium tuberculosis. • Molecules designed to inhibit the target enzyme, showed better in vitro antitubercular activity in Microplate Alamar Blue Assay (MABA). There is a correlation between the in silico molecular docking scores and In vitro antitubercular activity results. • The compounds AMA-3, AMA-4 & AMA-5 have the docking scores of -8.59, -8.68 & -8.05 Kcal/mol and were able to inhibit the growth of the organism even at the concentration of 12.5μg/ml. The Anti-tubercular activity of the compounds was found to be less superior than the Standard Anti-tubercular agents. • The molecules were also docked against the other critical enzymes of Mycobacterium tuberculosis. The obtained docking scores showed that the molecules were able to inhibit multiple enzymes which are necessary for the survival of the organism. • Therefore, further refinement of the molecular structure of the synthesized compounds will expected to yield promising drug candidates against the deadly disease.

Item Type: Thesis (Masters)
Additional Information: 2261915701
Uncontrolled Keywords: Design, Synthesis, Biological Evaluation, Novel Saccharin Derivatives, Anti-Tubercular Agents, Glutamine Synthetase.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Subramani R
Date Deposited: 02 Nov 2022 17:42
Last Modified: 03 Nov 2022 13:58

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