apigenin and Alzheimer-Disease

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Butyrylcholinesterase; Carbamates; Cell Line; Cell Survival; Cholinesterase Inhibitors; Copper; Dose-Response Relationship, Drug; Drug Development; Flavanones; Humans; Molecular Structure; Neuroprotective Agents; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apigenin; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Ligands; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Rats; Rivastigmine; Structure-Activity Relationship; Zebrafish

Topics: Acetylcholinesterase; Aluminum Chloride; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Drug Development; Humans; Ligands; Molecular Structure; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Structure-Activity Relationship; Zebrafish

Amyloid β (Aβ) aggregation plays an essential role in promoting the progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ aggregation is a potential therapeutic approach for AD. Herein, twenty-seven biflavonoids with different inter-flavonyl linkages and methoxy substitution patterns were isolated from several plants, and their Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Biflavonoids; Humans

Alzheimer's disease (AD) is the main cause of dementia in people over 65 years. One of the major culprits in AD is the self-aggregation of amyloid-β peptide (Aβ), which has stimulated the search for small molecules able to inhibit Aβ aggregation. In this context, we recently reported a simple, but effective in vitro cell-based assay to evaluate the potential antiaggregation activity of putative Aβ aggregation inhibitors. In this work this assay was used together with docking and molecular dynamics simulations to analyze the anti-Aβ aggregation activity of several naturally occurring flavonoids and phenolic compounds. The results showed that rosmarinic acid, melatonin, and o-vanillin displayed zero or low inhibitory capacity, curcumin was found to have an intermediate inhibitory potency, and apigenin and quercetin showed potent antiaggregation activity. Finally, the suitability of the combined in vitro cell-based/in silico approach to distinguish between active and inactive compounds was further assessed for an additional set of flavonols and dihydroflavonols.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Apigenin; Benzaldehydes; Cinnamates; Depsides; Flavonoids; Humans; In Vitro Techniques; Molecular Structure; Peptide Fragments; Phenols; Quercetin; Rosmarinic Acid

Glutaminyl cyclase (QC) plays an important role in the pathogenesis of Alzheimer's disease (AD) and can be a potential target for the development of novel anti-AD agents. However, the study of QC inhibitors are still less. Here, phenol-4' (R1-), C5-OH (R2-) and C7-OH (R3-) modified apigenin derivatives were synthesized as a new class of human QC (hQC) inhibitors. The efficacy investigation of these compounds was performed by spectrophotometric assessment and the structure-activity relationship (SAR) was evaluated. Molecular docking was also carried out to analyze the binding mode of the synthesized flavonoid to the active site of hQC.

Topics: Alzheimer Disease; Aminoacyltransferases; Enzyme Inhibitors; Flavonoids; Humans; Molecular Docking Simulation; Structure-Activity Relationship

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a new family of tacrine-4-oxo-4H-chromene hybrids has been designed, synthesized, and evaluated biologically. The tacrine fragment was selected for its inhibition of cholinesterases, and the flavonoid scaffold derived from 4-oxo-4H -chromene was chosen for its radical capture and β-secretase 1 (BACE-1) inhibitory activities. At nano- and picomolar concentrations, the new tacrine-4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase (h-AChE and h-BuChE), being more potent than the parent inhibitor, tacrine. They are also potent inhibitors of human BACE-1, better than the parent flavonoid, apigenin. They show interesting antioxidant properties and could be able to penetrate into the CNS according to the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent combined inhibition of human BACE-1 and ChEs, as well as good antioxidant and CNS-permeable properties.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Antioxidants; Aspartic Acid Endopeptidases; Benzopyrans; Blood-Brain Barrier; Butyrylcholinesterase; Catalytic Domain; Cattle; Cholinesterase Inhibitors; Chromones; Free Radical Scavengers; Humans; Membranes, Artificial; Permeability; Structure-Activity Relationship; Tacrine

Alzheimer disease is characterized by the abnormal aggregation of amyloid beta peptide into extracellular fibrillar deposits known as amyloid plaques. Soluble oligomers have been observed at early time points preceding fibril formation, and these oligomers have been implicated as the primary pathological species rather than the mature fibrils. A significant issue that remains to be resolved is whether amyloid oligomers are an obligate intermediate on the pathway to fibril formation or represent an alternate assembly pathway that may or may not lead to fiber formation. To determine whether amyloid beta oligomers are obligate intermediates in the fibrillization pathway, we characterized the mechanism of action of amyloid beta aggregation inhibitors in terms of oligomer and fibril formation. Based on their effects, the small molecules segregated into three distinct classes: compounds that inhibit oligomerization but not fibrillization, compounds that inhibit fibrillization but not oligomerization, and compounds that inhibit both. Several compounds selectively inhibited oligomerization at substoichiometric concentrations relative to amyloid beta monomer, with some active in the low nanomolar range. These results indicate that oligomers are not an obligate intermediate in the fibril formation pathway. In addition, these data suggest that small molecule inhibitors are useful for clarifying the mechanisms underlying protein aggregation and may represent potential therapeutic agents that target fundamental disease mechanisms.

Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Humans; Plaque, Amyloid; Protein Structure, Quaternary; Thermodynamics