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 VIc, VIf, VIg, VIi, and VIk have the highest antiproliferative activity. Compounds VIc, VIf, VIg, VIi, and VIk inhibited EGFR with IC₅₀ values ranging from 96 to 127 nM. Compounds VIf and VIk 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 VIk, 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, VIc, VIf, and VIk have a high capacity to inhibit LOX-IMVI cell line survival.

Graphical Abstract

HIGHLIGHTS

• A series of piperine-carboximidamide hybrids VIa-k was designed and synthesised.

• The new compounds were evaluated as antiproliferative agent targeting EGFR, BRAF, and CDK2.

• Antiproliferative activities were evaluated against four human cancer cell lines.

• Molecular docking studies were carried out against EGFR, mutated BRAF and CDK2-TK.

• In silico ADME/pharmacokinetic analysis was considered.

Keywords:

• Piperine
• amidoxime
• hybridisation
• antiproliferative
• kinases

Disclosure statement

The author reported no potential conflicts of interest(s).

Additional information

Funding

This work was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project Number [PNURSP2022R3], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.