Research Information System
Journal of Molecular Structure, vol.1347, 2025 (SCI-Expanded)
In the pursuit of novel therapeutic agents against Alzheimer's disease (AD), six N-acetyl Schiff base derivatives (F1-6), featuring a 1,2,4-triazole scaffold and sulfonate ester functionalities, are rationally designed, synthesized, and subjected to comprehensive biological and computational evaluation. Structural characterization was confirmed through FT-IR, UV-Vis, and NMR spectroscopy. Biological activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)—two critical enzymes in AD pathology—is assessed. Among the tested compounds, F2 and F5 demonstrated the most promising dual inhibitory profiles. F2 showed IC50 values of 3.05 µM (AChE) and 4.74 µM (BChE), with Ki values of 0.67 µM and 2.14 µM, respectively, indicating notable selectivity toward AChE (selectivity index, SI = 3.19). In contrast, F5 exhibited potent, balanced inhibition across both enzymes, with IC50 values of 2.06 µM (AChE) and 2.67 µM (BChE), and Ki values of 1.33 µM and 2.56 µM, resulting in a selectivity index (SI) of 1.92. These results suggest that both compounds are competitive inhibitors with superior potency compared to galantamine and rivastigmine, although slightly less potent than tacrine. Molecular docking studies revealed that F2 and F5 fit well into the active sites of both AChE and BChE, forming meaningful interactions with key aromatic residues. F2 displayed robust π–π stacking with Trp86 and Tyr337 in AChE and with Trp82 and Phe329 in BChE. Meanwhile, the F5 shows significant π–π interactions with Tyr124, Tyr341, and Phe295 in AChE, and Trp231 and Phe329 in BChE. These interaction patterns were supported by 200-ns molecular dynamics (MD) simulations, which confirmed the structural stability of both enzyme–ligand complexes through consistent root mean square deviation (RMSD) values of ∼1.5 Å and root mean square fluctuation (RMSF) values. Binding free energy calculations using MM-GBSA further validated the docking outcomes, with the F2-AChE complex exhibiting the most favorable binding energy (∼100 kcal/mol). Diffusion map analysis confirmed that this complex remained localized in a stable, low-energy conformational basin throughout the simulation. Electronic structure analysis via Density Functional Theory (DFT) at the B3LYP/6-311++G(d,p) level revealed that F2 possessed a HOMO–LUMO energy gap of 4.276 eV, indicating favorable electronic properties. Additional global reactivity descriptors—including a chemical potential of −4.455 eV, a softness of 0.468 eV-1, and an electrophilicity index of 4.640 eV—suggest high biological reactivity. Molecular electrostatic potential (MEP) mapping further pinpointed nucleophilic and electrophilic regions relevant for binding interactions. These integrated findings highlight F2 and F5 as potent dual cholinesterase inhibitors with competitive binding mechanisms, favorable pharmacodynamic properties, and promising structural features for further development. Future efforts will focus on optimizing their pharmacokinetic profiles and conducting in vivo efficacy and toxicity studies to further enhance their therapeutic potential.