Novel 4- Aryl-2(1H)-phthalazinone Derivatives as Cyclooxygenase-2 Inhibitors: Synthesis, Molecular Modeling Study and Evaluation as Promising Anti-inflammatory Agents.

BACKGROUND: Inflammation is a natural reaction of our body in response to infection or any other injury to renovate that damage. The majority of the available Non-steroidal anti-inflammatory drugs is nonselective and consequently, causes gastric irritation and ulceration. Therefore, it is a beard to design and synthesize a new series of Non-steroidal anti-inflammatory drugs with minimal gastric complications.

METHODS: A series of novel 4-(3,4-dimethylphenyl)-2(1H)-phthalazinone derivatives were designed, synthesized and evaluated for their in vivo anti-inflammatory activity. The compounds that showed powerful anti-inflammatory activities were assessed for their in vitro COX-1/COX-2 inhibitory activity and their in vivo ulcerogenic profile. The interaction between the designated compounds and the binding pocket of the COX-2 enzyme was predicted by molecular docking stimulation.

RESULTS: Six compounds, 2, 4, 5, 7a, 7b, and 8b showed significant anti-inflammatory activities at 4h compared to standard drug celecoxib. Compounds 4, 5, and 8b were the most potent and selective COX-2 inhibitors. Moreover, all the screened compounds demonstrated higher gastric safety profile compared to celecoxib particularly compound 8b displayed the highest safety profile. Among the tested compounds, 8b displayed the best fitting score, the highest antiinflammatory activity and COX-2 selectivity with minimal ulcer score.

CONCLUSION: A new series of phthalazinone derivatives were successfully synthesized and were evaluated for their in vivo anti-inflammatory activity. Six compounds (2, 4, 5, 7a, 7b, and 8b) presented powerful anti-inflammatory activity compared to celecoxib. Moreover, compounds 4, 5 and 8b were the most potent inhibitors to COX-2 and were inactive to COX-1. The screened compounds showed better ulcer protection and less gastric lesion compared to celecoxib. Compound 8b was the most promising candidate with more gastric safety.