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
Enzymatic browning, primarily catalyzed by polyphenol oxidase (PPO), is a major cause of postharvest losses and quality degradation in fresh-cut fruit and vegetable processing. To control this browning, conventional methods such as sulfite treatment and thermal inactivation have been widely used, yet they increasingly face safety, sensory, and regulatory concerns. Because of this, more attention has been directed toward natural PPO inhibitors from agro-industrial by-products as safer, value-added alternatives. However, current knowledge of PPO inhibition mechanisms and rational inhibitor discovery remains fragmented across the literature, limiting the development of effective and sustainable anti-browning approaches. To address this gap, this review presents an integrated framework that covers (i) the structural and kinetic basis of PPO catalysis at the binuclear copper active site; (ii) the mechanistic classification of reversible and irreversible inhibitors, together with kinetic characterization using IC50, Ki, and nonlinear regression approaches; (iii) computational screening strategies, including molecular docking and molecular dynamics simulations as modern tools for predicting enzyme–inhibitor interactions and prioritizing candidate inhibitors; and (iv) the potential of agro-industrial by-products as renewable sources of natural PPO inhibitors for extending the shelf life of fresh-cut produce. Through this framework, this review provides an integrated perspective to support the rational evaluation and future development of effective, sustainable PPO inhibitors for food processing.
H. T. Tran, X. Tran, Hoang Duy Huynh et al.· Catalysts· 0 citations
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