ap-2238 and Alzheimer-Disease

Acetylcholinesterase (AChE) enzyme inhibition is an important target for the management of Alzheimer disease (AD) and AChE inhibitors are the main stay drugs for its management. Coumarins are the phytochemicals with wide range of biological activities including AChE inhibition. The scientists have attempted to explore the coumarin template for synthesizing novel AChE inhibitors with additional pharmacological activities including decrease in beta-amyloid (Aβ) deposition and beta-secretase inhibition that are also important for AD management. Most of the designed schemes have involved incorporation of a catalytic site interacting moiety at 3- and 4-positions of the coumarin ring. The present review describes these differently synthesized coumarin derivatives as AChE inhibitors for management of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinesterase Inhibitors; Coumarins; Humans; Models, Molecular

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Binding Sites; Calcium Channel Blockers; Chelating Agents; Cholinesterase Inhibitors; Humans; Huntington Disease; Ligands; Multiple Sclerosis; Neurodegenerative Diseases; Neurofibrillary Tangles; Neurotransmitter Agents; Parkinson Disease; Plaque, Amyloid

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Benzylamines; Blood-Retinal Barrier; Butyrylcholinesterase; Cell Death; Cholinergic Agents; Cholinesterase Inhibitors; Cinnamates; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Rats; Structure-Activity Relationship

We report on a series of hybrid compounds structurally derived from donepezil and AP2238. This study was aimed at improving the activities of the reference compounds, donepezil and AP2238, and at broadening the range of activities of new derivatives as, due to the multifactorial nature of AD, molecules that modulate the activity of a single protein target are unable to significantly modify the progression of the disease. In particular, the indanone core from donepezil was linked to the phenyl-N-methylbenzylamino moiety from AP2238, through a double bond that was kept to evaluate the role of a lower flexibility in the biological activities. Moreover, SAR studies were performed to evaluate the role of different substituents in position 5 or 6 of the indanone ring in the interaction with the PAS, introducing also alkyl chains of different lengths carrying different amines at one end. Derivatives 21 and 22 proved to be the most active within the series and their potencies against AChE were in the same order of magnitude of the reference compounds. Compounds 15, 21-22, with a 5-carbon alkyl chain bearing an amino moiety at one end, better contacting the PAS, remarkably improved the inhibition of AChE-induced Abeta aggregation with respect to the reference compounds. They also showed activity against self-aggregation of Abeta(42) peptide, the most amyloidogenic form of amyloid produced in AD brains, while the reference compounds resulted completely ineffective.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Binding Sites; Bleomycin; Cholinesterase Inhibitors; Computer Simulation; Coumarins; Donepezil; Humans; Indans; Lomustine; Methotrexate; Peptide Fragments; Piperidines; Recombinant Proteins; Stilbenes; Structure-Activity Relationship; Tetrahydronaphthalenes

The complex etiology of Alzheimer's disease (AD) prompts scientists to develop multifunctional compounds to combat causes and symptoms of such neurodegeneration. To this aim we designed, synthesized, and tested a series of compounds by introducing halophenylalkylamidic functions on the scaffold of AP2238, which is a dual binding site acetylcholinesterase inhibitor. The inhibitory activity was successfully extended to the beta-site amyloid precursor protein cleavage enzyme, leading to the discovery of a potent inhibitor of this enzyme (3) and affording multifunctional compounds (2, 6, 8) for the treatment of AD.

Topics: Alzheimer Disease; Amides; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cholinesterase Inhibitors; Coumarins; Drug Design; Humans; Models, Molecular; Protease Inhibitors

In recent years, the investigation of acetylcholinesterase (AChE) inhibitors has gained further interest, because the involvement of the peripheral site of the enzyme in the beta-amyloid (Abeta) aggregation process has been disclosed. We present here, for the first time, a direct evidence of the Abeta antiaggregating action of an AChE inhibitor (AP2238) purposely designed to bind at both the catalytic and the peripheral sites of the human enzyme.

Topics: Acetylcholinesterase; Acetylthiocholine; Alzheimer Disease; Amyloid beta-Peptides; Benzopyrans; Benzylamines; Butyrylcholinesterase; Catalytic Domain; Cholinesterase Inhibitors; Coumarins; Fluorometry; Humans; Hydrolysis; Models, Molecular; Structure-Activity Relationship