Novel Bis-Sulfonate Schiff Base Derivatives as Dual AChE Inhibitors and Antimicrobial Agents: Synthesis and Molecular Docking Studies

A series of bis-sulfonate Schiff base derivatives were synthesized by the condensation of substituted 4-formylphenyl benzenesulfonates with 1,5-diaminopentane. The resulting products were obtained in high purity and fully characterized by IR, 1H and 13C NMR analyses, followed by molecular docking and molecular dynamics studies. The compounds were evaluated for their antimicrobial and acetylcholinesterase (AChE) inhibitory activities, revealing a clear substituent-dependent structure–activity relationship. Among them, {[pentane-1,5-diylbis(azanylylidene)]bis(methanylylidene)}bis(4,1-phenylene)bis(4-nitrobenzenesulfonate), bearing a nitro group, showed the most potent AChE inhibition (IC50 = 0.3 µM), comparable to galantamine (0.4 µM), and exhibited broad-spectrum antimicrobial activity (MIC = 156–625 µg/mL). {[Pentane-1,5-diylbis(azanylylidene)]bis(methanylylidene)}bis(4,1-phenylene)bis(4-chlorobenzenesulfonate) and {[pentane-1,5-diylbis(azanylylidene)]bis(methanylylidene)}bis(4,1-phenylene)bis(4-fluorobenzenesulfonate) presented notable AChE inhibition, while electron-donating substituents decreased activity. Structure-based docking, 100 ns all-atom molecular dynamics simulations, and MM/PBSA free-energy calculations consistently supported {[pentane-1,5-diylbis(azanylylidene)]bis(methanylylidene)}bis(4,1-phenylene) bis(4-nitrobenzenesulfonate) as the most promising inhibitor, displaying a stable binding mode within the catalytic and peripheral anionic sites and a favorable binding free energy (ΔGbind = –38.02 kcal/mol). Overall, these findings identify {[pentane-1,5-diylbis(azanylylidene)]bis(methanylylidene)}bis(4,1-phenylene)bis(4-nitrobenzenesulfonate) as a dual-active lead molecule and provide valuable insights for the rational design of next-generation AChE inhibitors and antimicrobial agents.