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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

[ Vol. 15 , Issue. 3 ]

Author(s):

Saghir Abbas, Sumera Zaib, Shafiq Ur Rahman, Saqib Ali*, Shahid Hameed, Muhammad Nawaz Tahir, Khurram Shahzad Munawar, Farzana Shaheen, Syed Mustansar Abbas and Jamshed Iqbal*   Pages 298 - 310 ( 13 )

Abstract:


Background: The over-expression of the carbonic anhydrases results in some specific carcinomas including pancreatic, gastric and brain tumor. Tumors are distinguished under hypoxic conditions and various investigations are being carried out to target the known hypoxic areas of the tumors 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 to evaluate 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 for their inhibitory potential against carbonic anhydrase II by in vitro assay. Double reciprocal plots for inhibition kinetics of the potent compounds were constructed and mode of inhibition was determined. Furthermore, to check the cytotoxicity, these derivatives were tested against human breast adenocarcinoma by MTT method.

Results: X-ray diffraction analysis of the compounds 10, 14 and 15 showed that they did not have any π-π or C-H…π interactions. The experimental results were validated by molecular docking and dynamic simulations of the potent compounds in the active pocket of enzyme. Important binding interactions of potent compounds with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Drug likeness profile of the derivatives was evaluated to determine the physicochemical properties.

Conclusion: The proposed synthetic approach provides a suitable platform for the generation of a new library of compounds which could potentially be employed in the future testing and optimization of inhibitor potencies.

Keywords:

1, 2, 4-triazole-3-thione, Schiff base, X-ray crystallography, Molecular docking, Dynamic simulations.

Affiliation:

Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad, Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad-22060, Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad-22060, Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad, Department of Chemistry, Quaid-I-Azam University, 45320, Islamabad, Department of Physics, University of Sargodha, Sargodha, Department of Chemistry, University of Sargodha, Mianwali Campus, Department of Chemistry, Allama Iqbal Open University, Islamabad, Department of Energy and Materials Engineering, Dongguk University, 30, Pildong-ro 1 gil, Jung-gu, Seoul 100- 715, Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad-22060



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