Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: Anti-inflammatory and analgesic activities

• A new series of cyclic imides was synthesized.
• Compounds 6a, 6b, 7a and 7b exhibit optimal COX-2 inhibitory potency.
• Compound 6a showed superior anti-inflammatory activity relative to diclofenac.
• Compound 6a showed superior analgesic activity relative to celecoxib.

A group of 30 cyclic imides (1–10a-c) was designed for evaluation as a selective COX-2 inhibitor and investigated in vivo for anti-inflammatory and analgesic activities. Compounds 6a, 6b, 7a and 7b exhibit optimal COX-2 inhibitory potency (IC50 = 0.18, 0.24, 0.28 and 0.36 μM; respectively) and selectivity index (SI) range of 363–668. In vitro COX-1/COX-2 inhibition structure–activity studies identified compound 6a as a highly potent (IC50 = 0.18 μM), and an extremely selective [COX-2 (SI) = 668] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50 = 54.0 mg/kg) relative to diclofenac (ED50 = 114 mg/kg). Molecular Docking study of the synthesized compound 6a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. Docking study showed that the methoxy moeities of 6a inserted deep inside the 2°-pocket of the COX-2 active site, where the O-atoms of such groups underwent an H-bonding interaction with His90 (3.02 Å), Arg513 (1.94, 2.83 Å), and Gln192 (3.25 Å).

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