| Summary: | In the pursuit of developing more potent and effective targeted kinase inhibitors (TKIs), a series of new compounds, specifically halogenated ‘(<i>E</i>)-4-((7<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-4-yl)amino)-<i>N</i>’-benzylidenebenzohydrazides’, were successfully synthesized in three steps with high yields. Among these novel compounds, namely <b>5e</b>, <b>5h</b>, <b>5k</b>, and <b>5l</b>, promising cytotoxic effects were observed against four different cancer cell lines, with IC<sub>50</sub> values ranging from 29 to 59 µM. Notably, compound <b>5k</b> emerged as the most potent inhibitor, exhibiting significant activity against EGFR, Her2, VEGFR2, and CDK2 enzymes, with IC<sub>50</sub> values ranging from 40 to 204 nM, comparable to the well-known TKI sunitinib (IC<sub>50</sub> = 261 nM). Mechanistic investigations of compound <b>5k</b> revealed its ability to induce cell cycle arrest and apoptosis in HepG2 cells, accompanied by a notable increase in proapoptotic proteins caspase-3 and Bax, as well as the downregulation of Bcl-2 activity. Furthermore, molecular docking studies indicated similar binding interactions between compound <b>5k</b> and the four enzymes, as observed with sunitinib. These findings highlight the potential of compound <b>5k</b> as a promising candidate for further development as a multi-targeted kinase inhibitor with enhanced potency.
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