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oai:ebyu-rdlopen.rawdatalibrary.net:ebyu/109762026-10-18T21:13:11Zopenairedrivercom_ebyu_10000col_ebyu_10001

Molecular and structural characterization of ureido-benzenesulfonamides as dual inhibitors of aldose reductase and cholinesterasesTürkeş, CüneytLolak, NebihDuran, Hatice EsraYapar, GönülAkocak, SuleymanAldose reductaseCholinesterase inhibitionMolecular dockingStructure-activity relationshipUreido-benzenesulfonamidesAcetylcholinesteraseAldehyde ReductaseAnimalsButyrylcholinesteraseCholinesterase InhibitorsEnzyme InhibitorsHumansMolecular Docking SimulationSulfonamides3 [3 (3 chlorophenyl)ureido]benzenesulfonamide3 [3 (3 tolyl)ureido]benzenesulfonamide3 [3 (3,4 dichlorophenyl)ureido]benzenesulfonamide3 [3 (4 chlorophenyl)ureido]benzenesulfonamide3 [3 (4 fluorophenyl)ureido]benzenesulfonamide3 [3 (4 tolyl)ureido]benzenesulfonamide4 [3 (3 chlorophenyl)ureido]benzenesulfonamide4 [3 (3 tolyl)ureido]benzenesulfonamide4 [3 (3,4 dichlorophenyl)ureido]benzenesulfonamide4 [3 (4 chlorophenyl)ureido]benzenesulfonamide4 [3 (4 fluorophenyl)ureido]benzenesulfonamide4 [3 (4 tolyl)ureido]benzenesulfonamidealdose reductase inhibitorbenzenesulfonamide derivativecholinesterasecholinesterase inhibitorThe conformational and kinetic intricacies of enzyme-ligand interactions are critical for understanding molecular mechanisms underlying metabolic and neurodegenerative pathologies. Herein, we report a rationally designed series of ureido-benzenesulfonamides as dual-acting nanomolar inhibitors targeting aldose reductase (ALR2) and cholinesterases (AChE and BChE). Spectrophotometric inhibition assays revealed that compound 3SA-a displayed exceptional ALR2 affinity (KI = 7.00 ± 0.68 nM), surpassing epalrestat by over 30-fold. Likewise, 3SA-f selectively inhibited BChE with a KI of 24.20 ± 2.26 nM, outperforming tacrine by a factor of 7.8. Molecular docking simulations highlighted distinct dynamic binding modes: 3SA-a engaged ALR2's catalytic cleft through a hydrogen bond with Tyr48 and water-bridged interactions, whereas 3SA-f leveraged π-π stacking and halogen bonding within BChE's extended acyl pocket. These binding orientations were consistent with SAR findings, where meta-sulfonamide placement and halogen substitution optimized selectivity and conformational complementarity. Complementary in silico ADME-Tox predictions confirmed the drug-like nature of all compounds (0 Lipinski/PAINS violations), moderate oral permeability (QPPCaco: 79–85 nm/s), and low CNS exposure (CNS score = −2), aligning with a peripheral mechanism of action. Collectively, this study provides a detailed structural and dynamic framework for dual-target enzyme inhibition, offering a tunable scaffold for future therapeutics targeting the ALR2-ChE axis. © 2025 Elsevier Inc.Academic Press Inc.2025Articlehttps://rdlopen.rawdatalibrary.net/r/ebyu/10976https://doi.org/10.1016/j.abb.2025.1105940003-9861enArchives of Biochemistry and Biophysicsinfo:eu-repo/semantics/openAccessinfo:eu-repo/semantics/articlehttps://ebyu-rdlopen.rawdatalibrary.net/tr/items/ebyu/10976