Novel pyrimidine-pyridine hybrids: Synthesis, cyclooxygenase inhibition, anti-inflammatory activity and ulcerogenic liability

• Published in: Bioorganic chemistry Vol. 77; pp. 339 - 348
• Main Authors: Abdelgawad, Mohamed A., Bakr, Rania B., Azouz, Amany A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2018
• Subjects: Animals; Anti-inflammatory activity; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cox isoforms; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Edema - drug therapy; Male; Molecular Docking Simulation; Molecular Structure; Pyridine derivatives; Pyridines - administration & dosage; Pyridines - chemistry; Pyridines - pharmacology; Pyrimidine derivatives; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Rats, Wistar; Structure-Activity Relationship; Ulcer - drug therapy; Ulcerogenic studies; Cox isoforms; Pyrimidine derivatives; Anti-inflammatory activity; Ulcerogenic studies; Pyridine derivatives
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.01.028

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•Compound 11c was the most active with edema inhibitory percent = 74% after 1 h.•The target compounds were detected to be selective inhibitors to COX-2 than COX-1.•9b, 9d and 11c revealed better COX-2 inhibitory activity than celecoxib.•All compounds were less ulcerogenic than indomethacin and comparable to celecoxib.•9d and 11c were subjected to molecular modeling simulation study.•The pyridine moiety combined with pyrimidine scaffold in one hybrid structure.•The scaffold affords a potential drug design concept for the development of NSAIDs.•The scaffold has a good anti-inflammatory with low ulcerogenic side effect.
Some derivatives containing pyrido[2,3-d:6,5d′]dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti-inflammatory effect of these candidates was determined and the ulcer indices were calculated for active compounds. 7-Amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (11c) exhibited better edema inhibition than celecoxib. Moreover, compounds 9b, 9d and 11c revealed better COX-2 inhibitory activity in a range (IC50 = 0.25–0.89 µM) than celecoxib (IC50 = 1.11 µM). Regarding ulcerogenic liability, all of the compounds under the study were less ulcerogenic than indomethacin. Molecular docking studies had been carried on active candidates 9d and 11c to explore action mode of these candidates as leads for discovering other anti-inflammatory agents.