Hybrids of Benzenesulfonamide Oxadiazole Derivatives with Dual CA II and COX-2 Inhibitory Activity Demonstrating Antiglaucoma and Anti-inflammatory Action: Synthesis, In Silico Insights, and In Vitro and In Vivo Bioevaluation.

In this study, new sulfonamide derivatives 5a-g and 10a-e were designed, synthesized, and biologically evaluated for their anti-inflammatory activity. In vitro COX inhibitory assays were performed, and among the synthesized compounds, 5b and 5d emerged as the most promising leads, combining COX-2 inhibition with remarkable selectivity (COX-2 IC50 = 0.13 and 0.05 μM, SI = 9.25 and 12.02, respectively) and hCA II inhibition (Ki = 39.1 nM and 62.6 nM, respectively) with a high selectivity index over hCA I (SI = 933.8 and 704.2, respectively). In vivo evaluations confirmed that compounds 5b and 5d (50 mg/kg) possess promising analgesic and anti-inflammatory effects, with rapid onset, sustained duration of action, and a reduced ulcerogenic liability, indicating an improved gastrointestinal safety profile. Additionally, 5b showed significant and sustained IOP-lowering effects in antiglaucoma animal models. Computational studies and X-ray crystallography were performed as a proof of concept.