scutellarein and Alzheimer-Disease

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Drug Design; Humans; Mice; Neuroprotective Agents; Rats; Structure-Activity Relationship

Topics: Acetylcholinesterase; Alzheimer Disease; Amino Acids; Amyloid beta-Peptides; Animals; Antioxidants; Apigenin; Carbamates; Cholinesterase Inhibitors; Drug Design; Glucuronates; Mice; Neuroprotective Agents; Rats; Structure-Activity Relationship

A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced Aβ(1-42) aggregation, Cu(2+)-induced Aβ(1-42) aggregation, human AChE-induced Aβ(1-40) aggregation and disassembled Cu(2+)-induced aggregation of the well-structured Aβ(1-42) fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study.

Topics: Acetylcholinesterase; Alzheimer Disease; Amines; Amyloid beta-Peptides; Animals; Antioxidants; Apigenin; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Hydrogen Peroxide; Memory Disorders; Mice; Models, Molecular; Molecular Structure; PC12 Cells; Peptide Fragments; Rats; Scopolamine; Structure-Activity Relationship

A series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed drug design strategy for treatment of Alzheimer's disease. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metals chelation, and neuroprotective effects against hydrogen peroxide-induced PC12 cell injury were evaluated in vitro. The preliminary results indicated that compound 7b exhibited good inhibitory potency toward AChE and BuChE with IC50 values of 1.2 ± 0.03 μm and 22.1 ± 0.15 μm, respectively, possessed the strong antioxidant potency (10.3 trolox equivalents), as well as acted as a selective metal chelator and neuroprotective agent. Furthermore, 7b could improve memory impairment induced by scopolamine, ethanol, and sodium nitrite using the step-down passive avoidance task in vivo and could remarkably decrease the activity of acetylcholinesterase in mice brain. This study indicated that 7b could be considered as a potential multitarget agent against AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Apigenin; Brain; Butyrylcholinesterase; Carbamates; Chelating Agents; Cholinesterase Inhibitors; Drug Design; Female; Humans; Male; Memory; Mice; Molecular Targeted Therapy; Neuroprotective Agents; PC12 Cells; Rats