Neuroprotective Potential of Aminonaphthoquinone Derivatives Against Amyloid Beta-Induced Neuronal Cell Death Through Modulation of SIRT1 and BACE1

Alzheimer's disease (AD) is characterized by the accumulation of tau protein tangles and amyloid-β (Aβ) plaques in the central nervous system (CNS), leading to progressive neurodegeneration. Hence, the discovery of disease-modifying agents capable of delaying the progression is essential for effective management. Aminonaphthoquinone (ANQ) is an attractive pharmacophore with various biological effects. This study explores the neuroprotective potentials of ANQ derivatives (1-18) using in vitro models of AD pathology (i.e., Aβ₄₂-induced SH-SY5Y cells). Findings demonstrated that all compounds mitigated Aβ₄₂-induced cellular damage by preserving cell viability and morphology. Among all, four compounds (10, 12, 16, and 18) showed potent antioxidant activities as well as abilities to minimize AD-related damages (i.e. decreasing intracellular reactive oxygen species (ROS) production, preserving mitochondrial membrane potential (MMP), protecting membrane damage, and modulating beta-secretase 1 (BACE1) activity) with comparable protective effects to the well-known neuroprotectant, resveratrol (RSV). A molecular docking study indicated these compounds could suitably bind to sirtuin 1 (SIRT1) protein with preferable affinity. Key amino acid residues and key functional groups essential for binding interactions were revealed. Target prediction identified a list of possible AD-related targets of these compounds offering insights into their mechanisms of action and suggesting their multifunctional potentials. Additionally, in silico predictions revealed that these candidates showed favorable drug-like properties. Overall, this study highlighted the therapeutic potential of ANQ derivatives in AD treatment, emphasizing the need for further experimental validation and comprehensive investigations to fully realize their therapeutic benefits.