Mohamed A Abdelgawad1, Mohammad M Al-Sanea1, Arafa Musa2, Mohammed Elmowafy3, Ashraf K El-Damasy4, Amany A Azouz5, Mohammed M Ghoneim6, Rania B Bakr7. 1. Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Al Jouf, 72341, Saudi Arabia. 2. Department of Pharmacognosy, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia. 3. Department of Pharmaceutics, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia. 4. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. 5. Department of Pharmacology and Toxicology, Beni-Suef University, Beni-Suef, 62514, Egypt. 6. Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah, 13713, Saudi Arabia. 7. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni- Suef, 62514, Egypt.
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-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.
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-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.
Authors: Renata B Lacerda; Cleverton K F de Lima; Leandro L da Silva; Nelilma C Romeiro; Ana Luisa P Miranda; Eliezer J Barreiro; Carlos A M Fraga Journal: Bioorg Med Chem Date: 2008-11-17 Impact factor: 3.641
Authors: Mariam Azzam Alanazi; Wael A A Arafa; Ibrahim O Althobaiti; Hamud A Altaleb; Rania B Bakr; Nadia A A Elkanzi Journal: ACS Omega Date: 2022-07-27