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

Abstract

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 <b>VIc</b>, <b>VIf</b>, <b>VIg</b>, <b>VIi</b>, and <b>VIk</b> have the highest antiproliferative activity. Compounds <b>VIc</b>, <b>VIf</b>, <b>VIg</b>, <b>VIi</b>, and <b>VIk</b> inhibited EGFR with IC₅₀ values ranging from 96 to 127 nM. Compounds <b>VIf</b> and <b>VIk</b> had the most potent inhibitory activity as BRAF^V600E (IC₅₀ = 49 and 40 nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI₅₀ = 44 and 35 nM against four cancer cell lines, respectively). Compound <b>VIk</b>, the most effective derivative as an antiproliferative agent, demonstrated potent anti-CDK2 action with an IC₅₀ value of 12 nM, which is 1.5-fold more potent than the reference dinaciclib. Finally, <b>VIc</b>, <b>VIf</b>, and <b>VIk</b> have a high capacity to inhibit LOX-IMVI cell line survival.