New amidrazone analogs as multi-kinase inhibitors: in-silico and biological investigation as an anticancer agent

Abstract

A series of novel biphenyl- and naphthyl-based amidrazone derivatives was synthesized and evaluated for anticancer activity against breast (MDA-MB-231) and colon (HL-60) cancer cell lines. Seven piperazine-containing derivatives exhibited significant anticancer effects with IC₅₀ values ranging from 7 to 30 μM while showing low toxicity toward fibroblasts (IC₅₀ > 300 μM). Molecular docking studies revealed that the most active compounds, 10a and 10e, bind strongly within the ATP-binding site of c-Abl kinase (PDB: 1IEP, resolution: 2.10 Å), achieving LibDock scores of 64.26 and 87.68, respectively, and enzyme inhibition IC₅₀ values of 18.29 μM and 10.28 μM. Compounds 12b, 12c, 12e, and 15b significantly inhibited PKN2 activity, while 12d and 16d showed enhanced potency against IKKβ despite lower c-Abl inhibition. These findings indicate that the anticancer effects of the synthesized derivatives are likely mediated by multitarget kinase inhibition, underscoring their promise as candidates for developing multi-kinase-targeting anticancer agents.