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

Graphical abstract Highlights • 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. Abstract 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 (ED 50) of 34.3–49.8 mg kg−1 and 63.6–86.6% edema inhibition relative to the reference drug celecoxib (ED 50 : 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 K I 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. [ABSTRACT FROM AUTHOR]