Design, synthesis of novel isoindoline hybrids as COX-2 inhibitors: Anti-inflammatory, analgesic activities and docking study

A group of novel isoindoline hybrids incorporating oxime, hydrazone, pyrazole, chalcone or aminosulfonyl pharmacophores (9-14) was designed and characterized by spectral data and elemental analyses results. All newly synthesized compounds were evaluated as COX-2 inhibitors, anti-inflammatory and analgesic agents. Six hybrid derivatives (10b, 10c, 11a, 11d, 13, 14) were moderate COX-2 inhibitors (IC₅₀ = 0.11-0.18 µM) close to standard celecoxib (IC₅₀ = 0.09 µM). The most active compounds showed outstanding in vivo anti-inflammatory activity (% edema inhibition = 41.7-50, 1 h; 40.7-67.4, 3 h; 20-46.7, 6 h) better than reference drug diclofenac (% edema inhibition = 29.2, 1 h; 22.2, 3 h; 20, 6 h). Most compounds showed significant peripheral and/or central analgesic activity. The moderate selective COX-2 inhibitor; dimethoxychalcone 11d (SI = 103) displayed excellent anti-inflammatory activity (% edema inhibition = 45.8-59.3) and increased thermal pain threshold (50-92.85%) comparable to piroxicam (75%). Molecular docking studies have been established.