Synthesis of novel bromophenolic sulfonamides with their acetylcholinesterase and carbonic anhydrase inhibitory actions.

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 BBr3 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 (Kᵢ = 23.52 nM) and AChE (Kᵢ = 2.29 nM), exhibiting a 12.7 and 21.9-fold better inhibitory effect than the reference inhibitors acetazolamide (Kᵢ = 298.15 nM) and tacrine (Kᵢ = 50.21 nM), respectively. Similarly, N-benzyl-2-bromo-4,5-dihydroxybenzenesulfonamide displayed potent dual inhibition against hCA I (Kᵢ: 53.62 nM) and AChE (Kᵢ: 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.