Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway.

A new series of piperine-carboximidamide hybrids VIa-k was developed as a new cytotoxic agent targeting EGFR, BRAF, and CDK2. The antiproliferative effect against four cancer cells was investigated against erlotinib. Hybrids VIc , VIf , VIg , VIi , and VIk have the highest antiproliferative activity. Compounds VIc , VIf , VIg , VIi , and VIk inhibited EGFR with IC 50 values ranging from 96 to 127 nM. Compounds VIf and VIk had the most potent inhibitory activity as BRAF V600E (IC 50 = 49 and 40 nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI 50 = 44 and 35 nM against four cancer cell lines, respectively). Compound VIk , the most effective derivative as an antiproliferative agent, demonstrated potent anti-CDK2 action with an IC 50 value of 12 nM, which is 1.5-fold more potent than the reference dinaciclib. Finally, VIc , VIf , and VIk have a high capacity to inhibit LOX-IMVI cell line survival.