Docking Study, Synthesis, and Anti-Inflammatory Potential of Some New Pyridopyrimidine-Derived Compounds

Abstract

Mohamed A Abdelgawad,1 Mohammad M Al-Sanea,1 Arafa Musa,2 Mohammed Elmowafy,3 Ashraf K El-Damasy,4 Amany A Azouz,5 Mohammed M Ghoneim,6 Rania R Bakr7 1Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf, 72341, Saudi Arabia; 2Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia; 3Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia; 4Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; 5Department of Pharmacology and Toxicology, Beni-Suef University, Beni-Suef, 62514, Egypt; 6Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, 13713, Saudi Arabia; 7Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni- Suef, 62514, EgyptCorrespondence: Mohamed A Abdelgawad, Tel [phone], Fax [phone], Email [email protected]; [email protected] 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-1H-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 (IC50 = 0.67– 1.02 μM) comparing to celecoxib (IC50 = 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

Keywords

• cyclooxygenase inhibitors
• anti-inflammatory activity
• ulcerogenic effects
• tricyclic pyridopyrimidines