1,2,3-Triazole Tagged 3H-Pyrano[2,3-d]pyrimidine-6-carboxylate Derivatives: Synthesis, in Vitro Cytotoxicity, Molecular Docking and DNA Interaction Studies.

Abstract

A series of novel ethyl 2,7-dimethyl-4-oxo-3-[(1-phenyl-1H-1,2,3-triazol-4-yl)methyl]-4,5-dihydro-3H-pyrano[2,3-d]pyrimidine-6-carboxylate derivatives 7a - 7m were efficiently synthesized employing click chemistry approach and evaluated for in vitro cytotoxic activity against four tumor cell lines: A549 (human lung adenocarcinoma cell line), HepG2 (human hematoma), MCF-7 (human breast adenocarcinoma), and SKOV3 (human ovarian carcinoma cell line). Among the compounds tested, the compounds 7a, 7b, 7f, 7l, and 7m have shown potential and selective activity against human lung adenocarcinoma cell line (A549) with IC50 ranging from 0.69 to 6.74 μm. Molecular docking studies revealed that the compounds 7a, 7b, 7f, 7l, and 7m are potent inhibitors of human DNA topoisomerase-II and also showed compliance with stranded parameters of drug likeness. The calculated binding constants, kb , from UV/VIS absorptional binding studies of 7a and 7l with CT-DNA were 10.77 × 104 , 6.48 × 104 , respectively. Viscosity measurements revealed that the binding could be surface binding mainly due to groove binding. DNA cleavage study showed that 7a and 7l have the potential to cleave pBR322 plasmid DNA without any external agents.