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

[Display omitted] •Novel isoindoline-1,3-dione hybrids were designed and synthesized.•Designed compounds were screened for COXs inhibition and were more selective towards COX-2.•Six hybrid derivatives showed high potency as anti-inflammatory agents over diclofenac.•Most compounds displayed promising peripheral and/or central analgesic activities. 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.