Abstract
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.
Highlights
Cancer is a multifactorial disease, arising from the uncontrolled proliferation of a cell with the potential to invade to other organs of the body [1]
PI3Kα is one of the proto-oncogenes, which has a vital role in the regulation of many important cell signaling pathways including cellular replication, cell proliferation leading to growth and apoptosis [2, 3]
Considerable evidence suggest that PI3K (P110α) subunit protein is expected to mutate in these cancers that bring about constitutive downstream pathways leading to defective control of cellular proliferation and malignant transformation, PI3Kα is drawing attention in cancer biology [5,6]
Summary
Cancer is a multifactorial disease, arising from the uncontrolled proliferation of a cell with the potential to invade to other organs of the body [1]. Pyrazole derivatives have been reported to show a broad spectrum of biological activity including antibacterial [13], antifungal [14], analgesic [15], anti-inflammatory [16,17,18], neuroprotective [19], estrogen receptor binding [20], antineoplastic [21], activities. Due to their wide range of biological activities, pyrazoles received considerable interest in the field of drug discovery and pyrazole ring constitutes a relevant synthetic target in the pharmaceutical industry. Inspired by the biological properties of both pyrazole and triazole heterocycles in the present study, we thought of synchronizing both these moieties into a single molecule in order to obtain new hybrid molecules with improved biological activity and low toxicity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
