Synthesis and anti-inflammatory activity of sulfonamides and carboxylates incorporating trimellitimides: Dual cyclooxygenase/carbonic anhydrase inhibitory actions

[Display omitted] •Synthesis of trimellitimides incorporating benzenesulfonamides and carboxylates.•Anti-inflammatory, ulcerogenic and cyctotoxic activities were studied.•The derivatives were investigated as COX-1/2 inhibitors.•The derivatives were elucidated as hCA I, II, IV and IX inhibitors.•Sulfonamide derivatives exhibited the best inhibitory activity against COX-2 and CA. Trimellitimides 6–21 were prepared and investigated in vivo for anti-inflammatory and ulcerogenic effects and in vitro for cytotoxicity. They were subjected to in vitro cyclooxygenase (COX-1/2) and carbonic anhydrase inhibition protocols. Compounds 6–11 and 18 exhibited anti-inflammatory activities and had median effective doses (ED50) of 34.3–49.8 mg kg−1 and 63.6–86.6% edema inhibition relative to the reference drug celecoxib (ED50: 33.9 mg kg−1 and 85.2% edema inhibition). Compounds 6–11 and 18 were weakly cytotoxic at 10 μM against 59 cell lines compared with the reference standard 5-fluorouracil (5-FU). Compounds 6–11 had optimal selectivity against COX-2. The selectivity index (SI) range was >200–490 and was comparable to that for celecoxib [COX-2 (SI) > 416.7]. In contrast, compounds 12, 13, and 16–18 were nonselective COX inhibitors with a selectivity index range of 0.92–0.25. The carbonic anhydrase inhibition assay showed that sulfonamide incorporating trimellitimides 6–11 inhibited the cytosolic isoforms hCA I and hCA II, and tumor-associated isoform hCA IX. They were relatively more susceptible to inhibition by compounds 8, 9, and 11. The KI ranges were 54.1–81.9 nM for hCA I, 25.9–55.1 nM for hCA II, and 46.0–348.3 nM for hCA IX. © 2018 Elsevier Science. All rights reserved.