Design, synthesis and antiproliferative activity of functionalized flavone-triazole-tetrahydropyran conjugates against human cancer cell lines

•Novel flavone-triazole-tetrahydropyran conjugates were synthesized.•Compounds 3c, 3g, 3i–j, 4c and 4h showed excellent cytotoxicity (IC50 0.61–1.68 μM) against the tested cell lines.•Compounds 4a and 4e showed excellent cytotoxicity (IC50 0.70–1.45 μM) against MDA-MB 231, KCL22 cells.•Compounds 3a, 3d, 3e and 4g showed excellent cytotoxicity (IC50 0.90–1.54 μM) against HeLa cells.

Under optimized reaction conditions, an efficient synthetic method has been developed to afford the functionalized flavone-triazole-tetrahydropyran conjugates via click reactions. The Cu-catalyzed 1,3-dipolar cycloaddition reaction gave the pure products, 5-iodo- and 5-H-1-(tetrahydropyran)-1,2,3-triazol-4-(3-methoxylflavone) derivatives in excellent yield (90–98%) within 1–3 h. Further, Pd-catalyzed Suzuki coupling of 5-iodo-1,2,3-triazoles with phenylboronic acids afforded 5-phenyl-1-(tetrahydropyran)-1,2,3-triazol-4-(3-methoxylflavone) derivatives in excellent yield (93–95%) in 4–5 h. Products (3a–l, 4a–j) were screened in vitro for their anti-proliferative activity against three human cancer cell lines (MDA-MB 231, KCL22 and Hela). Compounds 3c, 3g, 3i, 3j, 4c and 4h have shown better cytotoxicity (IC50 0.61–1.68 μM) than the reference drugs. Compounds 4e (IC50 0.70 μM), 3j (IC50 0.61 μM) and 4d (IC50 0.65 μM) exhibited anti-proliferative activity better than the reference drugs against the MDA-MB 231 cells, KCL22 cells and HeLa cells respectively.

Graphical abstractNovel flavone-triazole-tetrahydropyran conjugates were synthesized and screened for their anti-proliferative activity. Compounds 3c, 3g and 4h have shown better cytotoxic activity against the tested cell lines than the reference drugs, doxorubicin and FU.Figure optionsDownload full-size imageDownload as PowerPoint slide