Abstract
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•A series of indazole derivatives 6a-v as multi-targeted kinase inhibitors has been designed and synthesized.•Compounds 6f, 6i, 6j, 6 s, and 6n were the most active antiproliferative agents.•Compounds 6f, 6 s, and 6n display potent antiproliferative activity with strong inhibition of CDK-2/EGFR/c-Met.•Compounds 6f, 6 s, and 6n induced apoptosis and demonstrated overexpression for most of the apoptotic markers.•Docking study revealed high binding affinities toward targeted receptors.
Indazole is a significant class of heterocyclic compounds with a wide range of biological activity. We display here the synthesis and biological evaluation of a novel series of indazole derivatives 6a-v, which are differently substituted at the 6-position of the indazole moiety. The antiproliferative activity of compounds 6a-v was tested against four human cancer cell lines, using the MTT assay and doxorubicin as the reference drug. Compounds 6f, 6i, 6j, 6 s, and 6n were the most effective synthesized derivatives, with GI50 values of 0.77, 0.86, 1.05, 1.05, and 1.07 µM, respectively, against the 4 cell lines, in comparison to the control doxorubicin (GI50 = 1.10 µM). Compounds 6f, 6i, 6j, and 6 s the most potent derivatives as antiproliferative agents, displayed the utmost inhibitory activity against EGFR, and CDK2 and c-Met. Compounds 6f, 6n, and 6 s induced apoptosis through cytochrome C overexpression and activation of the intrinsic apoptotic pathway generated by the investigated compounds.