Design, Synthesis, and In Vitro Evaluation of Aromatic Sulfonamides as Human Carbonic Anhydrase I, II, IX, and XII Inhibitors and Their Antioxidant Activity

Abstract

This study is focused on the design, synthesis, and evaluation of some sulfonamide derivatives for their inhibitory effects on human carbonic anhydrase (hCA) enzymes I, II, IX, and XII as well as for their antioxidant activity. The purity of the synthesized molecules was confirmed by the HPLC purity analysis and was found in the range of 93%–100%. The inhibition constant (K_i) against hCA I ranged from 0.75 nM to 1972 nM. The sulfonamides inhibited isoform hCA II significantly, with a K_i ranging from 0.09 to 56 nM. Similarly, the inhibitory effects on hCA IX and XII were found with K_i spanning from 27.8 to 2099 nM and 9.43 to 509 nM, respectively. Most of the synthesized compounds showed significant inhibition in comparison to standard drugs such as acetazolamide, ethoxzolamide, zonisamide, methazolamide, dorzolamide, and SLC-0111. Antioxidant activity was assessed using the DPPH assay, with compound 13 showing better antioxidant activity with an IC₅₀ of 54.8 µg/mL, as compared to the standard ascorbic acid (IC₅₀ 64.7 µg/mL). The molecular docking studies provided insights into the binding modes of these compounds. The in silico physicochemical properties, pharmacokinetic/ADME, and toxicity properties evaluations confirmed favorable drug-likeness properties, complying with Lipinski's rule. These findings underscore the therapeutic potential of these compounds for the treatment of retinal/cerebral edema, glaucoma, edema, epilepsy management, high-altitude sickness, and cancer.