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.