Synthesis, structural characterization and biological evaluation of a novel pyrimidinetrione-chalcone sulphonamide as a COX-2-targeted scaffold.

The synthesis of a novel sulphonamide-chalcone pyrimidinetrione derivative, (E)-4-(3-oxo-3-(2,4,6-trioxohexahydropyrimidin-5-yl)prop-1-en-1-yl)-N-phenylbenzenesulfonamide was synthesized in a multi-steps method, with one of the reaction step being a solid-supported solvent-free method. IR, NMR, mass spectral analysis were done to confirm the molecular structure. Density functional theory (DFT) calculations have been performed to explore optimal geometry, electronic characteristics as well as conformational stability. The calculated value of HOMO-LUMO energy gap is 3.608 eV, which is a high kinetic stability, and the Frontier Molecular Orbital (FMO) reveals that there is an effective delocalization of charges throughout the chalcone-pyrimidinetrione structure. Potential Energy Surface (PES) scanning of the enone dihedral angle depicts that it has a global minimum of -1.70° (∼0 kcal/mol) corresponding to the s-cis conformer while maxima appear ±900 (∼8 kcal/mol). At the local minima at ±178° represent the s-trans conformer. Even though there is no significant difference in IR, UV-Vis and 1H NMR spectral features between both conformers, PES analysis shows that s-cis conformer is the most active form in terms of energy. The results of molecular docking indicated that the synthesized compound showed a high binding affinity with COX-2, BSA, and DNA with docking score of -11.55 kcal/mol, -12.1 kcal/mol, and - 4.34 kcal/mol as compared to standard celecoxib and pyrimidinetrione. Interaction with BSA and DNA was supported by UV-Vis and fluorescence spectroscopic analysis. The compound demonstrated potent cytotoxicity against MCF-7 (IC50: 2 μM) and A549 (IC50: 200 nM) cell lines, and exhibited antiangiogenic potential in the CAM assay. The localization of the nucleus in cancer cells was established using confocal imaging and found to have a good antioxidant activity in the DPPH assay. The COX-2 enzyme assay demonstrated approximately 75% inhibition, which supports its consistency with the molecular docking results.