Synthesis of Pyridine-Dicarboxamide-Cyclohexanone Derivatives: Anticancer and α-Glucosidase Inhibitory Activities and In Silico Study

An efficient and practical method for the synthesis of 2,6-diaryl-4-oxo-N,N′-di(pyridin-2-yl)cyclohexane-1,1-dicarboxamide is described in this present study, which occurs through a double Michael addition reaction between diamide and various dibenzalacetones. The reaction was carried out in dichloromethane (DCM) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The anticancer activities of the synthesized compounds were evaluated in several cancer cell lines, including MCF-7, MDA-MB-231, SAS, PC-3, HCT-116, HuH-7 and HepG2 cells. From these experiments, we determined that MDA-MB-231 was the most sensitive cancer cell line to the compounds 3c, 3e, 3d, 3j and 3l, which exhibited variable anticancer activities (3l [IC(50) = 5 ± 0.25 µM] > 3e [IC(50) = 5 ± 0.5 µM] > 3c [IC(50) = 7 ± 1.12 µM] > 3d [IC(50) = 18 ± 0.87 µM] > 3j [IC(50) = 45 ± 3 µM]). Of these, 3l (substituted p-trifluoromethylphenyl and chloropyridine) showed good potency (IC(50) = 6 ± 0.78 µM) against HCT-116 colorectal cancer cells and exhibited high toxicity against HuH-7 liver cancer cells (IC(50) = 4.5 ± 0.3 µM). These values were three times higher than the values reported for cisplatin (IC(50) of 8 ± 0.76 and 14.7 ± 0.5 µM against HCT-116 and HuH-7 cells, respectively). The highest α-glucosidase inhibitory activity was detected for the 3d, 3i and 3j compounds. The details of the binding mode of the active compounds were clarified by molecular docking studies.