RESUMEN
A series of phthalimide-donepezil (PTA-DPZ) hybrids (5a-e, 6a-l) were designed, synthesized and evaluated as selective inhibitors of acetylcholinesterase (AChE). The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration (IC50) at nanomolar range, which was better than the control drugs galanthamine and tacrine, and equivalent to DPZ. Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13 μmol·L-1. Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE. Moreover, some compounds could inhibit AChE-induced β-amyloid (Aβ) aggregation. In addition, absorption, distribution, metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value. These compounds, especially 6k, may be considered as a dual-functional lead compound for in-depth research.
RESUMEN
Mitochondrial oxidative stress has been recognized as a preliminary and critical factor that aggravates the pathological cascade of Alzheimer's disease, which induces the production of β-amyloid protein, upregulates the expression of phosphorylated tau protein and triggers oxidative damage to lipids, proteins and mitochondrial deoxyribonucleic acid. Central neurons are more vulnerable to oxidative stress than non-neuronal cells due to their high oxygen demand, abundant unsaturated fatty acids and antioxidant enzymes deficiency. On this account, this review introduces the causes of mitochondrial oxidative stress, and analyzes the important role of mitochondrial oxidative stress in the pathogenesis of Alzheimer's disease. Meanwhile, the review focuses on the design and intervention strategies of drug delivery systems targeting mitochondrial oxidative stress in neurons, aiming to provide new ideas for the prevention and treatment of Alzheimer's disease.