Design, Synthesis, Characterization and Biological Evaluation of Novel Pyridine-Thiadiazole Derivatives as Antitubercular Agents Targeting ATP Synthase

Karthikeyan, L (2021) Design, Synthesis, Characterization and Biological Evaluation of Novel Pyridine-Thiadiazole Derivatives as Antitubercular Agents Targeting ATP Synthase. Masters thesis, College of Pharmacy, Madras Medical College, Chennai.


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On the basis of literature survey, ATP synthase was selected as the antitubercular target for the study. The mechanism of action and reason for selecting ATP synthase was discussed in enzyme profile. A database of 500 molecules were designed based on literature review. ADME and In-silico druglikeness properties of the designed molecules were determined by using the MOLINSPIRATION® tool. The bioactivity prediction was determined using PASS online tool. The molecules were subjected to toxicity assessment by OSIRIS® property explorer tool. Then molecular docking was performed for the 500 molecules against the target protein ATP synthase using AutoDock 4.2.6®. Five molecules with good docking score [lower binding energy] and interactions were taken and optimized for the synthesis. The scheme for the synthesis was developed and the compounds were synthesized with satisfactory yield. Purity of the synthesized compounds was improved by doing recrystallization repeatedly and the purity was evaluated by TLC and melting point for the individual compounds. The characterization of the synthesized compounds was done using Infra-red spectroscopy, Nuclear Magnetic Resonance [1H NMR] spectroscopy methods and Liquid Chromatography- Mass spectrometric methods [LC-MS]. The compounds were screened for in-vitro anti-mycobacterial activity by Microplate Alamar Blue Assay [MABA]. The synthesized compounds showed sensitivity [Minimum Inhibitory Concentration] between 12.5μg/ml to 1.6μg/ml. Compound LK04 possess MIC of 6.25μg/ml and LK05 possess 1.6μg/ml. 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 LK05 is more potent than Pyrazinamide and equipotent to INH and Ethambutol. All compounds were found to be safe as per the acute toxicity study. CONCLUSION: The work concludes that the novel pyridine-thiadiazole derivatives inhibit the enzyme ATP synthase which is important for energy metabolism of Mycobacterium tuberculosis. All the 5 compounds gave docking score between -7 to -9 Kcal/mol which shows good binding affinity to ATP synthase The minimum inhibitory concentration of the 5 synthesized compounds against H37RV ranged from 12.5 to 1.6 μg/ml. The intermediate compound shows 25 μg/ml. The acute toxicity studies revealed that all the compounds found to be safe and non-toxic. Further, structural modification of LK05 is expected to yield promising molecules against the pathogen Mycobacterium tuberculosis. The assay using pathogenic strain and chronic toxicity are the future prospects of the work.

Item Type: Thesis (Masters)
Additional Information: 261915706
Uncontrolled Keywords: Design, Synthesis, Characterization, Biological Evaluation, Novel Pyridine-Thiadiazole Derivatives, Antitubercular Agents, Targeting, ATP Synthase.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Subramani R
Date Deposited: 02 Nov 2022 17:50
Last Modified: 31 May 2023 05:09

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