Synthetic modification of hydroxychavicol by Mannich reaction and alkyne–azide cycloaddition derivatives depicting cytotoxic potential

•Design, synthesis of two distinct derivatives of hydroxychavicol (1) by Mannich and alkyne–azide cycloaddition reaction.•Some aminoalkyl derivatives 6, 8 and 10 exhibited 3–10 fold more cytotoxic potential than 1 in five cancer cell lines.•Compound 6, consider most potent molecule among all having IC50 ∼ 1–16 μM in five cancer cell lines.

Here we report the design, synthesis and lead optimization of hydroxychavicol (1) a high yielding metabolite ubiquitously present in the Piper betel leaves with the significant cytotoxic activity. This is the first report to describe the synthetic strategies of two distinct series of hydroxychavicol by Mannich reaction (2–10) and alkyne–azide cycloaddition (11–20). Furthermore, all the synthesized derivatives along with parent compound were evaluated for their in-vitro cytotoxic and antiproliferative potential in several distinct cancers cell lines. Among all, the Mannich reaction derived molecules 6, 8 and 10 displayed more potent cytotoxic activities with IC50 value in a range from 3 to 9 μM, which were 7–10 fold more potent than 1 against five human cancer cell lines viz. HL-60, Mia PaCa-2, MCF-7, HEP G2 and SK-N-SH. Our results describe an efficient synthetic approach used to evaluate the structure activity relationship of 1 and its derivative in search of potential new anticancer agents.

Graphical abstractAminoalkyl and alkyne–azide cycloaddition derivatives of hydroxychavicol (1) were synthesized and screened for cytotoxic potential. Among all, the Mannich derived molecules 6, 8 and 10 were 3–10 fold more potent than 1.Figure optionsDownload full-size imageDownload as PowerPoint slide