Novel ethyl 2-hydrazineylidenethiazolidin-5-ylidene acetate clubbed with coumarinylthiazolyl pyrazole system as potential VEGFR-2 inhibitors and apoptosis inducer: synthesis, cytotoxic evaluation, cell cycle, autophagy, in silico ADMET and molecular docking studies

Abstract

Novel derivatives of ethyl 3-substituted-2-{4-oxo-2-(2-((3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazol-4-yl)methylene)hydrazineyl)thiazol-5(4H)-ylidene}acetate (5a–h) were synthesized and assessed for their cytotoxic potential against the liver cancer cell lines Huh-7 and HepG-2. Among these, compounds 5d and 5g demonstrated notable antiproliferative effects, which were benchmarked against the standard drug doxorubicin. To further understand the mechanisms behind their antiproliferative activity, compounds 5d and 5g were investigated for their impact on the cell cycle and their ability to induce apoptosis. They were found to induce significant cellular cycle arrest at the G1 phase. Besides, they potentially enhanced the cellular late apoptosis and reduced the cellular viability. In consent with the apoptosis results, compounds 5d and 5g displayed significant potential autophagic induction against the studied cancer cell lines. Further, both compounds 5d and 5g showed strong interactions with the VEGFR-2 receptor when they were studied using molecular docking. The ADMET prediction indicated that these bioactive compounds have the potential to serve as effective to fight liver cancer.