Benzene sulfonamide derivatives attenuate ethylene glycol–induced nephrolithiasis via carbonic anhydrase inhibition and downstream COX-2/NF-κB modulation

Abstract Benzene sulfonamide derivatives are well recognized as carbonic anhydrase (CA) inhibitors with potential therapeutic relevance in renal disorders. The present study investigated the anti-urolithiatic and anti-inflammatory effects of two benzene sulfonamide derivatives, SBCL (compound A) and SBF (compound B), in an ethylene glycol–induced rat model of nephrolithiasis, with a particular focus on CA inhibition and downstream modulation of inflammatory pathways. Male Wistar albino rats were allocated into control, nephrolithiasis, and treatment groups, and renal function, urinary lithogenic parameters, body and organ weights, and urine output were assessed. Pharmacokinetic profiles of both compounds were evaluated in serum, liver, kidney, and urine using a validated HPLC method. Mechanistic insights were obtained through in vitro carbonic anhydrase inhibition assays, molecular docking studies targeting renal CA isoforms, and immunohistochemical evaluation of cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB) expression in renal and hepatic tissues. Both SBCL and SBF significantly ameliorated ethylene glycol–induced nephrolithiasis, as evidenced by improved urinary biochemical profiles, enhanced diuresis, and attenuation of renal injury. SBCL exhibited stronger CA inhibitory potency and tighter binding within CA active sites, but with a narrower safety margin. In contrast, SBF demonstrated moderate CA inhibition alongside favorable pharmacokinetic behavior, enhanced urinary excretion, improved body weight recovery, and reduced hepatic oxidative burden. Immunohistochemical findings revealed marked suppression of COX-2 and NF-κB expression in treated animals, supporting downstream anti-inflammatory effects following CA modulation. Collectively, these results identify carbonic anhydrase inhibition as a central mechanism underlying the renoprotective effects of benzene sulfonamide derivatives, with SBF emerging as a more balanced therapeutic candidate combining adequate efficacy with improved safety and translational potential for nephrolithiasis management.