2-(4-hydroxyphenyl)-5-6-7-trimethoxy-4H-1-benzopyran-4-one and Alzheimer-Disease

A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Aβ

Topics: Alzheimer Disease; Animals; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Cholinesterases; Dose-Response Relationship, Drug; Drug Design; Flavones; Humans; Maze Learning; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; PC12 Cells; Rats; Scopolamine; Structure-Activity Relationship

A series of 5,6,7-trimethoxyflavone-6-chlorotacrine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that the target compounds exhibited good acetylcholinesterase (AChE) inhibitory potencies, high selectivity toward AChE over butyrylcholinesterase (BuChE), potential antioxidant activities and significant inhibitory potencies of self-induced beta-amyloid peptide (Aβ) aggregation. In particular, compound 14c had the strongest AChE inhibitory activity with IC50 value of 12.8 nM, potent inhibition of self-induced Aβ1-42 aggregation with inhibition ratio of 33.8% at 25 μM. Moreover, compound 14c acted as an antioxidant, as well as a neuroprotectant. Furthermore, 14c could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 14c might be a potential multifunctional candidate for the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Butyrylcholinesterase; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Electrophorus; Equidae; Flavones; Molecular Structure; PC12 Cells; Rats; Structure-Activity Relationship; Tacrine

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed ligand strategy. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metal-chelating properties and neuroprotective effects against hydrogen peroxide induced PC12 cell injury were evaluated in vitro. The results showed that most of the synthetic compounds exhibited good multifunctional activities. In particular, compound 15c exhibited dual inhibitory potency on acetylcholinesterase and butyrylcholinesterase with IC50 values of 0.57 and 22.6μM, respectively, and good antioxidative activity, with a value 1.3-fold of Trolox. In addition, 15c acted as a selective biometal chelator and possessed neuroprotective effects. Furthermore, 15c could cross the blood-brain barrier (BBB) in vitro and had significant neuroprotective effects in scopolamine-induced cognitive impairment in mice. Taken together, these results suggest that compound 15c might be a potential multifunctional agent for the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Apigenin; Blood-Brain Barrier; Butyrylcholinesterase; Carbamates; Cell Line; Chelating Agents; Cholinesterase Inhibitors; Cognition; Glucuronates; Humans; Mice; Molecular Docking Simulation; Neuroprotective Agents; Rats