Synthesis, cytotoxic assessment, and molecular docking studies of 2,6-diaryl-substituted pyridine and 3,4- dihydropyrimidine-2(1H)-one scaffolds

Abstract

Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reportedfor the synthesis of these derivatives, employing cobalt ferrite (CoFe 2 O4 @SiO2 -SO3 H) magnetic nanoparticles undermicrowave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessedagainst the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonickidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxicmolecule against the MCF-7 cell line (IC50 of 0.17 µg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showedexcellent cytotoxic activities against the AGS cell line, with an IC50 of 4.90 and 4.97 µg/mL, respectively. Althoughthey are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showedthat the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential ofthe candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridinederivatives, compound 5m had the most free energy of binding (–9.52 kcal/mol) and lowest Ki (0.105 µM), and amongthe pyrimidine derivatives, compound 4r had the most free energy of binding (–7.67 kcal/mol) and lowest Ki (2.39 µM).Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding sitevia H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM andpyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpfulin the further design of DHPMs and pyridine derivatives as potential anticancer agents.