The effect of benzenesulfonamide's side chains on their human carbonic anhydrase Ⅰ/Ⅱ inhibitory activities

Benzenesulfonamides are well-known potent carbonic anhydrase inhibitors (CAIs). They are usually composed of benzenesulfonamide heads and hydrophobic side chain tails. However, hydrophobic side chain tails contribute to poor water solubility, which is a major challenge in the development of CAIs. Herein, to elaborate whether benzenesulfonamides with hydrophilic/hydrophobic tails are effective against carbonic anhydrases (CAs), 12 benzenesulfonamides containing hydrophilic tails and 16 benzenesulfonamides containing hydrophobic tails were designed and synthesized. Benzenesulfonamides with hydrophilic tails including 4b, 4c, and 5b and benzenesulfonamides with hydrophobic tails including 2e, 4b, and 4c are potent carbonic anhydrase Ⅰ/Ⅱ dual inhibitors whose Ki to CA I and CA II were below 10 nM, and below 50 nM, respectively. However, the water solubility of 4b, 4c, and 5b was 52, 148, and 71 mg/100 g of water, respectively, which is much better than that of benzenesulfonamides with hydrophobic tails. In a hypoxic mouse model, compounds 4c and 5b extended the survival of mice by 34.46% and 28.23%, respectively, compared to the blank control. Treatment with 4c and 5b extended survival better than acetazolamide treatment did (16.86%). Moreover, 5b also has better anti-convulsant effect than AAZ. Molecular docking analysis demonstrated that hydrogen bonds between the oxygen atoms in the hydrophilic tails of 4b, 4c, and 5b and H 2 O in hCA I and hCA II protein facilitated ligand-receptor binding. Therefore, considering the good water solubility and potent CA I/II inhibition, 4c and 5b are worth exploring as therapeutic options for acute mountain sickness. In conclusion, benzenesulfonamides containing hydrophilic tails could offer innovative opportunities for potent, water-soluble anti-AMS (Acute Mountain Sickness) compounds.