Green Synthesis of Sulfonamide Derivatives as Human Carbonic Anhydrase Isoforms I, II, IX, XII Inhibitors and Antioxidants: Comprehensive Insights From Biological Evaluation and In‐Depth In Silico Analysis

: This study presents the green synthesis, pharmacological evaluation, and in silico analysis of aromatic sulfonamide derivatives for their inhibitory effects on human carbonic anhydrase (hCA) isoforms I, II, IX, and XII and their antioxidant properties. The compounds were synthesized via a one-step green synthetic method using acetic acid as the solvent, providing a straightforward and environmentally considerate approach. The synthesized compounds were confirmed to have 95% to 100% purities via HPLC purity analysis. The inhibition constants (Ki) against hCA I varied between 240 nM and 2185 nM, while inhibition of hCA II was observed with Ki values ranging from 19 to 83 nM. For hCA IX and hCA XII, the Ki values were found from 25 to 882 nM and 8.8 to 175 nM, respectively. These sulfonamides exhibited significant inhibition compared to standard carbonic anhydrase inhibitors such as acetazolamide, ethoxzolamide, zonisamide, methazolamide, dorzolamide, and SLC-0111. The antioxidant activity, assessed using the DPPH assay, was moderate to low, with compound 6 demonstrating a noteworthy IC50 of 62.8 µg/mL, comparable to the IC50 of ascorbic acid (64.7 µg/mL). Quantum chemical analyses, including FMO, Mulliken population analysis, and electrostatic potential, total electron density, and molecular electrostatic potential analysis, demonstrated significant electrostatic interactions and optimal charge distribution. DFT calculations revealed stable chemical behavior with favorable values for hardness, softness, electronegativity, and electrophilicity. Molecular docking studies provided insights into the binding interactions, while MD simulations (10 ns) revealed the stability of the protein-ligand complexes. ADMET predictions indicated favorable physicochemical properties and compliance with Lipinski's rule. These results highlight the potential of these aromatic sulfonamide derivatives as potent inhibitors of human carbonic anhydrase isoforms, with promising antioxidant activity, suggesting their potential therapeutic applications in conditions such as retinal and cerebral edema, glaucoma, epilepsy, high-altitude sickness, and cancer.