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Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors.
Bioorg Med Chem. 2017 11 01; 25(21):5929-5938.BM

Abstract

The present article describes the synthesis and enzyme inhibitory kinetics of methyl[2-(arylmethylene-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates 5a-j as mushroom tyrosinase inhibitors. The title compounds were synthesized via cyclocondensation of thiosemicarbazones 3a-j with dimethyl but-2-ynedioate (DMAD) 4 in good yields under solvent-free conditions. The synthesized compounds were evaluated for their potential to inhibit the activity of mushroom tyrosinase. It was unveiled that compounds 5i showed excellent enzyme inhibitory activity with IC50 3.17µM while IC50 of standard kojic acid is 15.91µM. The presence of heterocyclic pyridine ring in compound 5i play important role in enzyme inhibitory activity as rest of the functional groups are common in all synthesized compounds. The enzyme inhibitory kinetics of the most potent derivative 5i determined by Lineweaver-Burk plots and Dixon plots showed that it is non-competitive inhibitor with Ki value 1.5µM. It was further investigated that the wet lab results are in good agreement with the computational results. The molecular docking of the synthesized compounds was performed against tyrosinase protein (PDBID 2Y9X) to delineate ligand-protein interactions at molecular level. The docking results showed that the major interacting residues are His244, His85, His263, Val 283, His 296, Asn260, Val248, His260, His261 and Phe264 which are located in active binding site of the protein. The molecular modeling demonstrates that the oxygen atom of the compound 5i coordinated with the key residues in the active site of mushroom tyrosinase contribute significantly against inhibitory ability and diminishing the human melanin synthesis. These results evident that compound 5i is a lead structure in developing most potent mushroom tyrosinase inhibitors.

Authors+Show Affiliations

Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan.Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan. Electronic address: asaeed@qau.edu.pk.Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan.Department of Biochemistry & Biotechnology (Baghdad-ul-Jadeed Campus), The Islamia University of Bahawalpur, Bahawalpur, Pakistan.Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan. Electronic address: mzchem@yahoo.com.Florida Center of Heterocyclic Compounds, University of Florida, Gainesville, Fl 32601, USA; Center for Computationally Assisted Science and Technology, North Dakota State University, Fargo, ND 58102, USA.Department of Chemistry, Quaid-i-Azam University, 45320 Islamabad, Pakistan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28988751

Citation

Channar, Pervaiz Ali, et al. "Synthesis, Computational Studies and Enzyme Inhibitory Kinetics of Substituted Methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as Mushroom Tyrosinase Inhibitors." Bioorganic & Medicinal Chemistry, vol. 25, no. 21, 2017, pp. 5929-5938.
Channar PA, Saeed A, Larik FA, et al. Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors. Bioorg Med Chem. 2017;25(21):5929-5938.
Channar, P. A., Saeed, A., Larik, F. A., Rafiq, M., Ashraf, Z., Jabeen, F., & Fattah, T. A. (2017). Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors. Bioorganic & Medicinal Chemistry, 25(21), 5929-5938. https://doi.org/10.1016/j.bmc.2017.09.009
Channar PA, et al. Synthesis, Computational Studies and Enzyme Inhibitory Kinetics of Substituted Methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as Mushroom Tyrosinase Inhibitors. Bioorg Med Chem. 2017 11 1;25(21):5929-5938. PubMed PMID: 28988751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors. AU - Channar,Pervaiz Ali, AU - Saeed,Aamer, AU - Larik,Fayaz Ali, AU - Rafiq,Muhammad, AU - Ashraf,Zaman, AU - Jabeen,Farukh, AU - Fattah,Tanzeela Abdul, Y1 - 2017/09/18/ PY - 2017/06/09/received PY - 2017/08/02/revised PY - 2017/09/06/accepted PY - 2017/10/11/pubmed PY - 2017/11/29/medline PY - 2017/10/10/entrez KW - Kinetic mechanism KW - Molecular docking KW - Synthesis KW - Thiazolidinone KW - Tyrosinase inhibitors SP - 5929 EP - 5938 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 25 IS - 21 N2 - The present article describes the synthesis and enzyme inhibitory kinetics of methyl[2-(arylmethylene-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates 5a-j as mushroom tyrosinase inhibitors. The title compounds were synthesized via cyclocondensation of thiosemicarbazones 3a-j with dimethyl but-2-ynedioate (DMAD) 4 in good yields under solvent-free conditions. The synthesized compounds were evaluated for their potential to inhibit the activity of mushroom tyrosinase. It was unveiled that compounds 5i showed excellent enzyme inhibitory activity with IC50 3.17µM while IC50 of standard kojic acid is 15.91µM. The presence of heterocyclic pyridine ring in compound 5i play important role in enzyme inhibitory activity as rest of the functional groups are common in all synthesized compounds. The enzyme inhibitory kinetics of the most potent derivative 5i determined by Lineweaver-Burk plots and Dixon plots showed that it is non-competitive inhibitor with Ki value 1.5µM. It was further investigated that the wet lab results are in good agreement with the computational results. The molecular docking of the synthesized compounds was performed against tyrosinase protein (PDBID 2Y9X) to delineate ligand-protein interactions at molecular level. The docking results showed that the major interacting residues are His244, His85, His263, Val 283, His 296, Asn260, Val248, His260, His261 and Phe264 which are located in active binding site of the protein. The molecular modeling demonstrates that the oxygen atom of the compound 5i coordinated with the key residues in the active site of mushroom tyrosinase contribute significantly against inhibitory ability and diminishing the human melanin synthesis. These results evident that compound 5i is a lead structure in developing most potent mushroom tyrosinase inhibitors. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/28988751/Synthesis_computational_studies_and_enzyme_inhibitory_kinetics_of_substituted_methyl[2__4_dimethylamino_benzylidene__hydrazono__4_oxo_thiazolidin_5_ylidene]acetates_as_mushroom_tyrosinase_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(17)31217-8 DB - PRIME DP - Unbound Medicine ER -