Gayathri, S (2021) Design, Synthesis, Characterization and Biological Evaluation of Novel Quinoline-Thiadiazole Derivatives as Antitubercular Agents Targeting ATP Synthase. Masters thesis, College of Pharmacy, Madras Medical College, Chennai.
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Abstract
ATP synthase was selected as the anti-tubercular target for the study based on the assessment of various medicinal chemistry journals. In the enzyme profile, the mechanism of action and reason for selecting ATP synthase was discussed. • Based on the literature review, the database of 500 molecules were designed. • ADME and In-silico drug-likeness properties of the designed molecules were determined by using the MOLINSPIRATION®tool. • The bioactivity prediction of the designed molecules were determined by using PASS ONLINE software. • Then the molecules were subjected to toxicity assessment by OSIRIS®property explorer tool. The results were coded as green colour which indicates the drug-likeness. • Then molecular docking was performed for the 500 molecules against the target protein ATP synthase (PDB ID-7JG5) using AutoDock 4.2.6®. • Six molecules with good docking score [lower binding energy] and interactions were taken and optimized for the synthesis. • The scheme for synthesis was developed and the compounds were synthesized with satisfactory yield(upto 75%). • Purification of the synthesized compound was improved by recrystallization repeatedly and the purity was evaluated by TLC and Melting point for the synthesized compounds. • The characterization of the synthesized compounds was done using Infraredspectroscopy. • Nuclear Magnetic Resonance [1HNMR] spectroscopy methods and • Liquid Chromatography-Mass spectrometric methods [LC-MS]. • The pure compounds were screened for in-vitro anti-mycobacterial activity by Microplate Alamar Blue Assay [MABA]. All the compounds showed a significant antimycobacterial activity. • The synthesized compounds showed sensitivity [Minimum Inhibitory Concentration] between 12.5μg/ml to 1.6μg/ml. Compound SC-02, possess MIC of 3.12μg/ml and SC-05 possess 1.6μg/ml. • To the standard drugs Streptomycin and Rifampicin show activity at 0.8μg/ml. INH and Ethambutol at 1.6μg/ml, Pyrazinamide at 3.125μg/ml concentrations in same assay procedure. • MIC values indicates that SC-02 is equipotent than Pyrazinamide which is 3.125μg/ml. • MIC values indicates that the compound SC-05 is superior than Pyrazinamide and equipotent than INH and Ethambutol. All compounds were found to be safe as per the acute toxicity study conducted on Albino rats over the period of 14 days. CONCLUSION: • Our work concludes that our synthesized novel Quinoline-Thiadiazole derivatives were effective in inhibiting the target enzyme ATP Synthase, which is important for the Energy metabolism of the Mycobacteria. • The designed compounds gave Docking score between -7.9 Kcal/mol and -8.2 KJ/mol. All the compounds inhibited the Mycobacterium tuberculosis at the range of 1.6 μg/ml to 50 μg/ml which is equipotent to the standard drugs such as INH, Ethambutol and superior than Pyrazinamide. • The acute toxicity studies revealed that all the compounds found to be safe and non-toxic. • The MABA test is carried out by using H37Rv strain which is non-pathogenic. Hence further studies should be carried out using pathogenic strains. • Therefore, further refinement of the molecular structure of the compounds is expected to yield promising drug candidates against the deadly mycobacteria.
| Item Type: | Thesis (Masters) |
|---|---|
| Additional Information: | 261915704 |
| Uncontrolled Keywords: | Design, Synthesis, Characterization, Biological Evaluation, Novel Quinoline-Thiadiazole Derivatives, Antitubercular Agents, Targeting, ATP Synthase. |
| Subjects: | PHARMACY > Pharmaceutical Chemistry |
| Depositing User: | Subramani R |
| Date Deposited: | 02 Nov 2022 17:47 |
| Last Modified: | 03 Nov 2022 14:18 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/20928 |
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