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 erloti-nib. Hybrids V-Ic, V-If, V-Ig, V-Ii, and V-Ik have the highest antiproliferative activity. Compounds V-Ic ,V-If, VIg, V-Ii, and V-Ik inhibited EGFR with IC50values ranging from 96 to 127nM. CompoundsVIfandVIkhad themost potent inhibitory activity as BRAFV600E(IC50=49 and 40nM, respectively) and were discovered to be potent inhibitors of cancer cell proliferation (GI(50)=44 and 35nM against four cancer cell lines, respectively). Compound V-Ik, the most effective derivative as an antiproliferative agent, demonstratedpotent anti-CDK2 action with an IC(50 )value of 12 nM, which is 1.5-fold more potent than the referencedinaciclib. Finally, V-Ic, V-If, andVIkhave a high capacity to inhibit LOX-IMVI cell line survival. [GRAPHICS] HIGHLIGHTS A series of piperine-carboximidamide hybridsVIa-kwas 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 silicoADME/pharmacokinetic analysis was considered.

Automated summary

A new series of piperine-carboximidamide hybrids were developed as cytotoxic agents targeting EGFR, BRAF, and CDK2, and showed promising antiproliferative activity. Several compounds exhibited potent inhibitory effects on cancer cell proliferation, specifically targeting EGFR, BRAFV600E, and CDK2. The study also highlighted the importance of molecular docking and in silico ADME/pharmacokinetic analysis in drug design.