Design, Synthesis And Bioactive Evaluation Of Pyrazolyl-thiazolinone Derivatives

EGFR and HER-2are the hottest targets in current cancer research and their overexpression or abnormal activation often cause cell malignant transformation. Compounds that inhibit the kinase activity of EGFR and/or HER-2after binding of its ATP binding site are of potential interest as new therapeutic antitumor agents. Gefitinib (Iressa) and erlotinib (Tarceva) are the representative drugs of this kind.The pyrazole motif makes up the core structure of numerous biologically active compounds, some showed potent EGFR and HER-2receptor tyrosine kinase inhibitory activity. Thiazolinone and their derivatives have attracted continuing interest over the years because of their varied biological activities. Recent years, thiazolinone derivatives with their antitumor activity have become a new hot spot.Herein, a series of pyrazolyl-thiazolinone derivatives (E1-E36) have been designed and synthesized and their biological activities were also evaluated as potential EGFR and HER-2kinase inhibitors. Thirty-four of the36compounds were reported for the first time. Among them, compound2-(5-(4-bromophenyl)-3-p-tolyl-4,5-dihydro-lH-pyrazol-l-yl)thiazol-4(5H)-one (E28) displayed the most potent inhibitory activity (IC50=0.24μM for EGFR and IC50=1.07μM for HER-2). Antiproliferative assay results indicated that compound E28owned high antiproliferative activity against MCF-7, B16-F10and HCT-116in vitro, with IC50 value of0.30,0.54, and0.70μM, respectively. Docking simulation was further performed to position compound E28into the EGFR active site to determine the probable binding model. Based on the preliminary results, compound E28with potent inhibitory activity in tumor growth would be a potential anticancer agent.Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of acute and chronic inflammatory diseases. However, the long-term clinical employment of NSAIDs is associated with significant side effects. The clinical efficacy of most NSAIDs is closely to their inhibition of cyclooxygenase (COXs), which catalyze the bioconversion of arachidonic acid (AA) to prostaglandins (PGs).Literature survey revealed that many pyrazole derivatives had been found their clinical application as NSAIDs. Among the highly marketed COX-2inhibitors that comprise the pyrazole nucleus, celecoxib is the one which is treated as a safe anti-inflammatory and analgesic agent. On the other hand, thiazolinone is an important class of heterocyclic compound, synthesis of the thiazolinones occupies an important place in the realm of synthetic pharmaceutical chemistry, due to their therapeutic and pharmacological properties. Some article had showed its effect on COX-2selectivity.A series of dihydro-pyrazolyl-thiazolinone derivatives (5a-5t) have been synthesized and their biological activities were also evaluated as potential cyclooxygenase-2(COX-2) inhibitors. Among these compounds, compound2-(3-(3,4-dimethylphenyl)-5-phenyl-4,5-dihydro-lH-pyrazol-l-yl)thiazol-4(5H)-one (5a) displayed the most potent COX-2inhibitory activity with IC50of0.5μM, but weak to COX-1. Docking simulation was performed to position compound5a into the COX-2active site to determine the probable binding model. Based on the preliminary results, compound5a with potent inhibitory activity and low toxicity would be a potential and selective anti-cyclooxygenase-2agent.