Synthesis of Coumarin-Thiazolidine-2,4-dione-Pyrazole Hybrids as Epidermal Growth Factor Receptor (EGFR)-Targeted Agents

摘要

Herein, we synthesized some new hybrids (5a-5o) containing coumarine, thiazolidine-2,4-dione and pyrazole entities using earlier developed Knoevenagel condensation and tandem acyl Sonogashira and cyclocondensation as key paths. All the hybrids in micromolar concentration were further evaluated for their in vitro cytotoxicity against four human cancer cell lines like MCF-7, A- 549, PC-3 and HeLa. Amongst the hybrids, compounds namely (Z)-5-((7-methoxy-2-oxo-2H-chromen-3-yl)methylene)-3-((3-(4-methoxyphenyl)-1H-pyrazol-5-yl)meth-yl)thiazolidine-2,4-dione (5d), (Z)-4-(5-((5-((7-methoxy-2-oxo-2H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)- 1H-pyrazol-3-yl)benzonitrile (5i), and (Z)-5-(5-((5-((7-methoxy-2-oxo-2H-chromen-3-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyl)-1H-pyrazol-3-yl)isophthalonitrile (5o) were found to be more active against all the cell lines than the standard doxorubicin with IC_(50) values less than 2 μM. As well, molecular docking studies revealed that five active compounds had good binding affinity towards the EGFR. Finally, the results of in vitro kinase inhibitory assay of compounds revealed that 5d (IC_(50) = 0.28 μM), 5i (IC_(50) = 0.26 μM) and 5o (IC_(50) = 0.25 μM) has more inhibiting power than Erlotinib.