SYNTHESIS, ANTICANCER EVALUATION AND MOLECULAR MODELING OF SOME SUBSTITUTED THIAZOLIDINONYL AND THIAZOLYL PYRAZOLE DERIVATIVES
Journal Title: International Journal of Pharmacy and Pharmaceutical Sciences - Year 2015, Vol 7, Issue 11
Abstract
Objective: The present work aimed to synthesize some new substituted thiazoles incorporated to pyrazole moiety starting from 1-(3-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-4-carboxaldehyde (1) in order to evaluate their anticancer activity and GSTP1 inhibition in a trail to explore new potential GST inhibitors and prevent the resistance of cells to anticancer drugs. In addition, investigate the probability of the most promising cytotoxic compounds to inhibit GSTP1 enzyme via molecular docking study.Methods: The carboxaldehyde 1 was treated with substituted thiosemicarbazide in absolute ethanol to give the corresponding thiosemicarbazone derivatives 2a–d. Cyclization of 2a-d either by ethyl bromoacetate, phenacyl bromide or maleic acid anhydride furnished new thiazole derivatives 3, 4 and 5, respectively. These target compound 2-5 were screened for their GSTP1 inhibition and cytotoxic activity against HEPG-2 (human liver carcinoma), A549 (human lung carcinoma) and PC3 (human prostate carcinoma). Finally, molecular docking study of the most promising cytotoxic compounds against GSTP1 (PDB ID: 3GUS) is discussed.Results: Compounds 4a, 4b, and 4d were found to be highly active against HEPG-2 and PC-3 cancer cell lines with IC50 values ranging from 0.2±0.81 to 9.3±2.08 μM compared to doxorubicin with IC50= 37.8±1.50 and 41.1±2.01 μM, respectively. Screening of 4a, 4b and 4d against GSTP1 showed higher inhibition activity with IC50 ranging from 1.5±0.18 to 4.3±0.29 μM. Docking studies revealed the promising binding affinities of the latter compounds which match with the binding mode of the ligand, NBDHEX toward the active site of GSTP1.Conclusion: Compounds 4a, 4b and 4d were distinguished by the higher anticancer activity against HEPG-2, A-549 and PC-3 cell lines of tumor and the remarkable inhibitory activity against GSTP1.
Authors and Affiliations
Eman S. Nossier, Salwa M. El-hallouty, Eman R. Zaki
Keywords
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