Synthesis and anticancer activity of new tetrahydroquinoline hybrid derivatives tethered to isoxazoline moiety

A new series of tetrahydroquinoline-isoxazoline hybrid derivatives (3a–p) were efficiently synthesized involving 1,3-dipolar cycloaddition reaction according to click chemistry approach, from the corresponding N-allyl-4-(2-oxopyrrolinidyl-1)-tetrahydroquinolines preformed, with moderate to good yields (63–77%). To establish new candidates with anticancer activity, the antiproliferative effect of these compounds was measured by the MTT assay on different cancer cell lines such as human breast adenocarcinoma (MCF-7), human liver carcinoma (HepG2), human lung adenocarcinoma (A549), cervical cancer (HeLa), and murine melanoma (B16F10). Compounds 3a (CC₅₀ = 11.37 μM, SI = 5.1) and 3i (CC₅₀ = 25.59 μM, SI > 4.6) showed the best anticancer activities against murine melanoma cells with considerable selectivity compared with VERO cells. Compound 3h showed the best anticancer activity on cervical cancer (HeLa) cells (CC₅₀ = 10.21 μM, SI = 4.1), and it was also slightly more active than the reference drug oxaliplatin. In addition, the compounds 3a and 3m decrease the mitochondrial membrane potential and induce apoptosis, suggesting that their cytotoxic effects may be based on mitochondrial parameter modulation.