Novel Schiff Base Sulfonate Derivatives as Carbonic Anhydrase and Acetylcholinesterase Inhibitors: Synthesis, Biological Activity, and Molecular Docking Insights

Sulfonate derivatives are an essential class of compounds with diverse pharmacological applications. This study presents the synthesis and detailed characterization of six novel Schiff base sulfonate derivatives (L1–L6) through spectroscopic techniques (FT-IR and NMR). Their inhibitory potential was evaluated against human carbonic anhydrase isoenzymes (hCA I and hCA II) and acetylcholinesterase (AChE), which are crucial therapeutic targets for diseases such as glaucoma, epilepsy, and Alzheimer's disease. The KI values for the compounds concerning AChE, hCA I, and hCA II enzymes were in the ranges of 106.10 ± 14.73 to 422.80 ± 17.64 nM (THA: 159.61 ± 8.41 nM), 116.90 ± 24.40 to 268.00 ± 35.84 nM (AAZ: 439.17 ± 9.30 nM), and 177.00 ± 35.03 to 435.20 ± 75.98 nM (AAZ: 98.28 ± 1.69 nM), respectively. Molecular docking analyses revealed key interactions within the active sites of the enzymes, including hydrogen bonding with critical residues and π–π stacking interactions. Notably, L3 demonstrated superior inhibition against hCA I (KI: 116.90 ± 24.40 nM) and AChE (KI: 106.10 ± 14.73 nM), positioning it as a promising lead compound. This comprehensive investigation contributes to the development of isoform-specific inhibitors for therapeutic use and provides valuable insights into their binding mechanisms. The findings underscore the potential of Schiff base sulfonates as scaffolds in drug discovery for neurodegenerative and metabolic disorders. © 2024 Wiley-VHCA AG, Zurich, Switzerland.