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

Abstract

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 [IC50 = 5 ± 0.25 µM] > 3e [IC50 = 5 ± 0.5 µM] > 3c [IC50 = 7 ± 1.12 µM] > 3d [IC50 = 18 ± 0.87 µM] > 3j [IC50 = 45 ± 3 µM]). Of these, 3l (substituted p-trifluoromethylphenyl and chloropyridine) showed good potency (IC50 = 6 ± 0.78 µM) against HCT-116 colorectal cancer cells and exhibited high toxicity against HuH-7 liver cancer cells (IC50 = 4.5 ± 0.3 µM). These values were three times higher than the values reported for cisplatin (IC50 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.

Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors

“…At the same time, the pyridine ring, present in many natural products and even genetic material, has been noted for its role in many biological processes as well as in cancer pathogenesis, which makes it a privileged scaffold in anticancer agents discovery 26 . Thus, there are reports of a variety of monosubstituted pyridines with cytotoxic activity [26][27][28][29] , and there are also several pyridyl-containing drugs introduced on the market for their antitumor properties 26 (Figure 1, right).…”

Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy

“…These results are evident that the designed fragments able to replicate the binding pattern to that of pralsetinib. In addition, the carboxamide and azaarene functional groups that were identified in the hit molecules were reported recently to have anticancer activity [ 45 , 46 ].…”

“…These results are evident that the designed fragments able to replicate the binding pattern to that of pralsetinib. In addition, the carboxamide and azaarene functional groups that were identified in the hit molecules were reported recently to have anticancer activity [45,46]. The ADMET analysis of the compounds was performed using the QikProp module of Schrödinger and ProTox-II software to prevent the elimination of molecules during clinical trials.…”

Discovery of a Potent Candidate for RET-Specific Non-Small-Cell Lung Cancer—A Combined In Silico and In Vitro Strategy

“…In the case of DB11982, a hydrogen bond formation between the pyridine carboxamide and ARG878 of RET protein was observed. It is interesting to note that the anticancer property of these functional groups of the hit compounds involved in the interaction with the RET protein has been reported recently [41][42][43]. The existence of interactions by the key residues ASN879 and ASP892 of hydrophobic pockets in RET proteins has also been observed in the other approved drugs, crizotinib, and sorafenib, respectively.…”