Oztaskin_2026_Bioorg.Med.Chem.Lett__130599

Because of the important biological properties of halogenated benzene sulfonamides, here we report the first synthesis of bromophenolic sulfonamides and their human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II) and acetylcholinesterase (AChE) inhibition. For this purpose, 4-bromo-1,2-dimethoxybenzene was reacted with chlorosulfonic acid fallowed by amination with ammonia, N-alkyl amines and N,N-dialkyl amines to give a series of novel sulfonamides. Subsequent O-demethylation of these sulfonamides using BBr(3) afforded the target bromophenolic benzene sulfonamides. The synthesized bromophenolic sulfonamides were evaluated for their inhibitory effects against both hCA I/II and AChE enzymes. Among these compounds, 2-bromo-4,5-dihydroxy-N-phenylbenzenesulfonamide showed the strongest inhibition against hCA II (K = 23.52 nM) and AChE (K = 2.29 nM), exhibiting a 12.7 and 21.9-fold better inhibitory effect than the reference inhibitors acetazolamide (K = 298.15 nM) and tacrine (K = 50.21 nM), respectively. Similarly, N-benzyl-2-bromo-4,5-dihydroxybenzenesulfonamide displayed potent dual inhibition against hCA I (K: 53.62 nM) and AChE (K: 2.91 nM). In addition, the computational findings obtained from in silico induced fit docking, ADME prediction, and molecular dynamics (MD) simulations further supported and validated the experimental inhibition results.