Synthesis and antiproliferative evaluation of new hybrids of piperine and acylhydrazone

Piperine, a natural amide isolated from the genus of <i>Piper</i>, serves as a pharmacophore in medicinal chemistry. In this study, we synthesised and evaluated 18 novel piperine-acylhydrazone hybrids (<b>4a</b>-<b>4r</b>) for their antiproliferative activities <i>in vitro</i>. The structures of these hybrids were validated using ¹H,¹³C NMR, and HR-ESI-MS data. Furthermore, we screened all synthesised compounds for their antiproliferative activities against three human cancer cell lines: FaDu (laryngeal carcinoma cells), HepG2 (hepatoblastoma carcinoma cells), and MGC803 (gastric carcinoma cells). Among them, compound <b>4o</b> exhibited significantly inhibitory activities against FaDu, HepG2, and MGC803 with IC₅₀ values of 13.85 ± 0.19, 11.02 ± 1.45, and 13.47 ± 3.43 <i>μ</i>M, respectively, which was approximately two-fold lower than the positive control cisplatin. These findings suggest that compound <b>4o</b> has the potential to be promising leads for the design of anti-cancer drugs.