Carbonic Anhydrase Inhibitory Potential of 1,2,4-triazole-3-thione Derivatives of Flurbiprofen, Ibuprofen and 4-tert-butylbenzoic Hydrazide: Design, Synthesis, Characterization, Biochemical Evaluation, Molecular Docking and Dynamic Simulation Studies

摘要

Background: The over-expression of the carbonic anhydrases results in some specificcarcinomas including pancreatic, gastric and brain tumor. Tumors are distinguished under hypoxicconditions and various investigations are being carried out to target the known hypoxic areas of thetumors to increase the sensitivity towards standard therapeutic treatment.Objective: Herein, we have designed and synthesized some biologically important esters, hydrazides,thiocarbamates, 1,2,4-triazole-3-thiones and Schiff bases. The purpose of the research was toevaluate the derivative against carbonic anhydrase and to assess the toxicity of the same compounds.Method: The structures of all the compounds were characterized by FT-IR, mass spectrometry,elemental analysis, 1H and 13C NMR spectroscopy. The synthetic derivatives were screened fortheir inhibitory potential against carbonic anhydrase II by in vitro assay. Double reciprocal plotsfor inhibition kinetics of the potent compounds were constructed and mode of inhibition was determined.Furthermore, to check the cytotoxicity, these derivatives were tested against humanbreast adenocarcinoma by MTT method.Results: X-ray diffraction analysis of the compounds 10, 14 and 15 showed that they did not haveany π-π or C-H…π interactions. The experimental results were validated by molecular docking anddynamic simulations of the potent compounds in the active pocket of enzyme. Important bindinginteractions of potent compounds with the key residues in the active site of the carbonic anhydraseenzyme were revealed. Drug likeness profile of the derivatives was evaluated to determine thephysicochemical properties.Conclusion: The proposed synthetic approach provides a suitable platform for the generation of anew library of compounds which could potentially be employed in the future testing and optimizationof inhibitor potencies.