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

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.