Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder requiring multi-target-directed ligands (MTDLs) to simultaneously modulate cholinergic dysfunction and amyloid-β pathology. In this study, a series of hydrazone-linked pyridin-1-ium salts was rationally designed and synthesized by integrating key pharmacophores of acetylcholinesterase (AChE) and β-secretase 1 (BACE-1) inhibitors into a compact scaffold. Biological evaluation revealed potent AChE inhibitory activity for most compounds, with several derivatives outperforming donepezil. Compound 8b exhibited the highest potency (IC50 = 0.026 ± 0.005 μM). Structure-activity relationship analysis indicated that small, moderately polar substituents enhanced AChE inhibition, whereas the introduction of bulkier groups into this series led to a relative improvement in BACE-1 inhibitory activity. Kinetic studies on AChE suggested a mixed-type inhibition mechanism. Molecular docking favored key π-π and π-cation interactions within the AChE gorge, while hydrophobic interactions contributed to BACE-1 binding. Complementing the static docking analysis, all-atom MD simulations further supported persistent residence of compound 8b within both AChE and BACE-1 binding sites, with interaction fingerprints refining the docking model by revealing dominant hydrophobic/π-π contacts in AChE and dynamic π-cation/hydrophobic contacts in BACE-1. In silico ADMET analysis demonstrated favorable drug-like properties. These findings highlight hydrazone-linked pyridin-1-ium salts as promising scaffolds for developing compact multi-targeted agents for AD.
Hoang Tran, L. Tien, H. Trần et al.· Bioorganic & Medicinal Chemi...· 0 citations
In this work, two previously undescribed sesquiterpenes, beilschmiedins A–B (1–2), as well as twelve known compounds (3–14), were obtained from the methanol extract of the Beilschmiedia percoriacea (B. percoriacea) leaves. Their structures were fully elucidated using a combination of spectroscopic techniques, including HR-ESI-MS, UV, and 1D/2D NMR, and compared with literature data. Furthermore, the absolute configurations of the new compounds 1 and 2 were determined by quantum chemical ECD calculations. Biologically, the fourteen isolates were evaluated for their anti-inflammatory, enzyme inhibitory, and antioxidant activities. Eleven compounds inhibited NO production more strongly than the positive control l-NAME. Among them, phillygenin (4), epi-pinoresinol (5), fargesin (6), and schisandlignan A (11) showed the most potent inhibitory effects (IC50 = 9.8–17.2 µM). In enzyme inhibition assays, schisandlignan A (11) and 3′,4′-dimethoxybenzoic acid (3″,4″-dimethoxyphenyl)-2-methyl-3-oxobutyl ester (14) exhibited exceptional α-glucosidase inhibitory potential (IC50 = 6.2 ± 0.38 and 5.0 ± 0.46 µM, respectively), significantly outperforming acarbose, while kobusin (7), forsythialan B (8), and nectandrin E (13) showed moderate xanthine oxidase inhibition (IC50 = 74.7–127.6 µM). For antioxidant activity, compound 5 possessed the strongest radical scavenging capacity, revealing that free phenolic hydroxyl groups enhanced potency. Furthermore, this study provides the first report of the anti-inflammatory activity of 11 and the α-glucosidase inhibition of 11 and 14, whereas the two new sesquiterpenes, 1 and 2, displayed only moderate anti-inflammatory effects and were inactive in the other assays. Molecular docking studies demonstrated that these bioactive compounds exhibit favorable binding affinities toward COX-2, XO, α-glucosidase, and Keap1, supporting their potential anti-inflammatory, antioxidant, antidiabetic, and anti-gout activities. The 200 ns molecular dynamics simulations further revealed stable complex behavior and limited structural deviation of the selected ligands within their respective binding sites.
Hieu Tran-Trung, Dau Xuan Duc, Chung Thi Nguyen et al.· RSC Advances· 0 citations
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