DESIGN, SYNTHESIS, MOLECULAR DOCKING, ADMET STUDIES AND BIOLOGICAL EVALUATION OF PYRAZOLINE INCORPORATED 1, 2, 3-TRIAZOLE BENZENE SULPHONAMIDES
Objective: The main objective of this work was to design, synthesize and evaluate the novel pyrazoline incorporated 1,2,3-triazole benzene sulphonamides for cytotoxic and anti-gout activities also to perform Insilco molecular docking studies.
Methods: Designed compounds were synthesized by condensation of different substituted chalcones (3a-i) with hydrazine hydrate and substituted phenylhydrazines. All the synthesized compounds were characterized on the basis of physical and spectral data. To predict the affinity and activity of the ligand molecule Libdock program was employed to generate different bioactive binding poses of designing molecules at the active site of protein Phosphatidylinositol 3-kinase (PI3Kα). Title compounds were evaluated for cytotoxic activity by using 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and anti-gout activity by potassium oxonate induced assay.
Results: All the synthesized compounds showed characteristic peaks in FTIR, 1H, 13C NMR and MASS spectral analysis. In molecular docking studies, compound 3i has shown good binding affinity to the active site of PI3Kα with a docking score of 145.031 and 4 hydrogen bonding interactions with least hepatotoxicity and good bioavailability when compared with that of reference ligand KKR exhibited a Libdock score of 88.35. Remaining compounds also have a good binding affinity with a minimum of 2 bonding interactions and having better absorption, distribution, metabolism, elimination and toxicity (ADMET) profile. The same compound (3i) exhibited the highest cytotoxic activity with an IC50 value of 4.54µg/ml. Compound 4d was evaluated for anti-inflammatory activity and it has significantly ameliorated against potassium oxonate induced gout in mice when compared with that of standard drug allopurinol due to its anti-inflammatory property.
Conclusion: We designed and synthesized a novel series of title compounds in quantitative yields and performed docking studies. New derivatives have a good binding affinity towards PI3Kα enzyme, good bioavailability, least hepatotoxicity and significant cytotoxic activity.
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