Docking Study, Synthesis, and Anti-Inflammatory Potential of Some New Pyridopyrimidine-Derived Compounds
Mohamed A Abdelgawad, Mohammad Al-Sanea, Arafa Musa, Mohammed Elmowafy, Ashraf K El-Damasy, Amany A Azouz, Mohammed M Ghoneim, Rania R Bakr
Abstract
Background and Purpose: Because of gastrointestinal irritation and kidney toxicity associated with non-steroidal anti-inflammatory drugs and the cardiovascular problems of Coxibs use, developing novel anti-inflammatory agents with reduced toxicity and improved selectivity remains a major challenge. Depending on our previous work, a novel series of pyridopyrimidinones IIIa-i has been synthesized via reaction of 6-amino-2-thioxo-2,3-dihydro-1 H -pyrimidin-4-one ( I ) and phenyldiazenyl aromatic aldehydes ( IIa-i ). All the new constructed compounds were fully characterized by elemental and spectral analysis. Methods: The target compounds IIIa–i were investigated for their potential towards COX inhibition, anti-inflammatory properties using carrageenan induced edema model in rat paw, and the ulcer indices of the most active members. Results: The ethyl pyridopyrmidinone-benzoates IIIf, IIIg and IIIh showed superior inhibitory activity of carrageenan induced edema to celecoxib. Furthermore, the pyridopyrimidinones IIId, IIIf, IIIg , and IIIi exerted improved COX-2 inhibitory activity (IC 50 = 0.67– 1.02 μM) comparing to celecoxib (IC 50 = 1.11 μM). Moreover, the gastric ulcerogenic potential assay of compounds IIIf – h revealed their lower ulcerogenic liability than indomethacin with comparable effect to celecoxib. Conclusion: Virtual docking investigation of the most active candidates IIId, IIIf, IIIg and IIIi in the active site of COX-2 enzyme showed that these compounds implied interaction and binding motif similar to the cocrystallized ligand bromocelecoxib. Keywords: cyclooxygenase inhibitors, anti-inflammatory activity, ulcerogenic effects, tricyclic pyridopyrimidines