piroxicam and Alzheimer-Disease

Butyrylcholinesterase (BuChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD). Development of selective BuChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Recently, we reported the N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (1) as a selective BuChE inhibitor. Subsequently, 33 analogs were synthesized and assessed by AChE/BuChE activities, indicating an optimal compound 23. Further kinetic tests suggested a competitive manner. Molecular docking and Molecular dynamics (MD) simulation showed that it interacted with several residues in active site gorge of BuChE, possibly contributing to its selectivity and competitive pattern. Moreover, it showed low cytotoxicity and high blood brain barrier (BBB) permeability. Taken together, 23 was a promising BuChE inhibitor for the treatment of AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Butyrylcholinesterase; Cell Line; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Models, Molecular; Molecular Structure; Structure-Activity Relationship

A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Binding Sites; Blood-Brain Barrier; Cholinesterase Inhibitors; Drug Design; Rats

Currently, of the few accessible symptomatic therapies for Alzheimer's disease (AD), memantine is the only N-methyl-d-aspartate receptor (NMDAR) blocker approved by the FDA. This work further explores a series of memantine analogs featuring a benzohomoadamantane scaffold. Most of the newly synthesized compounds block NMDARs in the micromolar range, but with lower potency than previously reported hit IIc, results that were supported by molecular dynamics simulations. Subsequently, electrophysiological studies with the more potent compounds allowed classification of IIc, a low micromolar, uncompetitive, voltage-dependent, NMDAR blocker, as a memantine-like compound. The excellent in vitro DMPK properties of IIc made it a promising candidate for in vivo studies in Caenorhabditis elegans (C. elegans) and in the 5XFAD mouse model of AD. Administration of IIc or memantine improved locomotion and rescues chemotaxis behavior in C. elegans. Furthermore, both compounds enhanced working memory in 5XFAD mice and modified NMDAR and CREB signaling, which may prevent synaptic dysfunction and modulate neurodegenerative progression.

Topics: Alzheimer Disease; Animals; Caenorhabditis elegans; Disease Models, Animal; Memantine; Mice; Receptors, N-Methyl-D-Aspartate

Cumulative evidence suggests that β-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Antioxidants; Aspartic Acid Endopeptidases; Azoles; Binding Sites; Blood-Brain Barrier; Cyclic S-Oxides; Drug Design; Humans; Interleukin-6; Isoindoles; Ligands; Mitochondria; Molecular Docking Simulation; Neuroprotective Agents; NF-E2-Related Factor 2; Organoselenium Compounds; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species; Selenium; Signal Transduction; Thiadiazines

Topics: Alzheimer Disease; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Dyrk Kinases; Glycogen Synthase Kinase 3 beta; Harmine; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Structure-Activity Relationship

Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Binding Sites; Blood-Brain Barrier; Butyrylcholinesterase; Cannabidiol; Carbamates; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Drug Design; Humans; Kinetics; Maze Learning; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Neuroprotective Agents; Structure-Activity Relationship

A series of resveratrol dimer derivatives against Alzheimer's disease (AD) was obtained by structural modification and transformation using resveratrol as substrate. Biological analysis revealed that these derivatives had moderate inhibitory activity against human monoamine oxidase B (hMAO-B). In particular, 3 and 7 showed the better inhibitory activity for hMAO-B (IC

Topics: Alzheimer Disease; Animals; Antioxidants; Blood-Brain Barrier; Cell Line; Dimerization; Humans; Mice; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Oxidative Stress; Prenylation; Rats; Resveratrol; Structure-Activity Relationship

Considering the importance of PDE4D inhibition and the modulation of biometals in Alzheimer's disease (AD) therapeutics, we have designed, synthesized and evaluated a series of new clioquinol-rolipram/roflumilast hybrids as multitarget-directed ligands for the treatment of AD. In vitro studies demonstrated that some of the molecules processed remarkable inhibitory activity against phosphodiesterase 4D (PDE4D), strong intracellular antioxidant capacity, potent inhibition of metal-induced aggregation of Aβ, and potential blood-brain barrier permeability. Compound 7a demonstrated significant improvement in cognitive and spatial memory in an Aβ

Topics: Alzheimer Disease; Aminopyridines; Animals; Benzamides; Clioquinol; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Drug Design; Humans; Ligands; Mice; Rats; Rolipram

A series of 4'-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Cell Line; Cholinesterase Inhibitors; Drug Design; Drug Discovery; Electrophorus; Flurbiprofen; Humans; Mannich Bases; Molecular Docking Simulation; Peptide Fragments; Protein Aggregates; Rats; Swine

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Chalcones; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Eels; Female; Horses; Humans; Male; Maze Learning; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Peptide Fragments; Protein Aggregates; Rats; Structure-Activity Relationship

A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Chalcone; Cholinesterase Inhibitors; Drug Design; Eels; Horses; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Peptide Fragments; Protein Aggregates

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC

Topics: Acetylcholinesterase; Adamantane; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Molecular Structure; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Structure-Activity Relationship; Tacrine

A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Cholinesterases; Donepezil; Drug Design; Drug Development; Humans; Kinetics; Models, Molecular; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship

A series of novel chalcone-O-alkylamine derivatives were designed, synthesized and evaluated as multifunctional anti-Alzheimer's disease agents. Based on the experimental results, compound 23c exhibited good inhibitory potency on both acetylcholinesterase (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Biological Transport; Blood-Brain Barrier; Butyrylcholinesterase; Chalcones; Chelating Agents; Cholinesterase Inhibitors; Coordination Complexes; Copper; Drug Design; Female; Humans; Male; Memory Disorders; Mice; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroprotective Agents; Protein Binding; Scopolamine; Structure-Activity Relationship

A series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-3) were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy, and their potential was evaluated through various biological experiments. Among these derivatives, compound 1b displayed good selective inhibitory activity against AChE (vs BuChE, IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Cognitive Dysfunction; Dose-Response Relationship, Drug; Drug Discovery; Humans; Imidazoles; Mice; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; Propylamines; Pyrimidines; Rats; Scopolamine; Structure-Activity Relationship; Thiourea

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Line, Tumor; Cholinesterase Inhibitors; Coumarins; Dose-Response Relationship, Drug; Drug Design; Humans; Kinetics; Male; Mice; Mice, Inbred Strains; Models, Molecular; Molecular Structure; Peptide Fragments; Protein Aggregates; Range of Motion, Articular; Structure-Activity Relationship; Thiocarbamates

A series of 4'-OH-flurbiprofen-chalcone hybrids were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Cell Line; Cell Survival; Chalcones; Chelating Agents; Copper; Drug Design; Flurbiprofen; Humans; Lipopolysaccharides; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Nitric Oxide; Peptide Fragments; Recombinant Proteins; Structure-Activity Relationship

A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Benzylamines; Blood-Brain Barrier; Cholinesterase Inhibitors; Drug Design; Humans; Kinetics; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Permeability; Protein Aggregates; Recombinant Proteins; Structure-Activity Relationship; Thiazoles

Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Butyrylcholinesterase; Cell Line; Cholinesterase Inhibitors; Cricetulus; Dose-Response Relationship, Drug; Humans; Molecular Structure; Quinolines; Structure-Activity Relationship; Tacrine

Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodone-tacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Depression; Drug Design; Ligands; Mice; Permeability; Serotonin 5-HT1 Receptor Agonists; Structure-Activity Relationship; Tacrine; Vilazodone Hydrochloride

There has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC

Topics: Alzheimer Disease; Blood-Brain Barrier; Cholinesterase Inhibitors; Cholinesterases; Chromones; Drug Design; Hep G2 Cells; Humans; Ligands; Molecular Docking Simulation; Molecular Targeted Therapy; Monoamine Oxidase; Monoamine Oxidase Inhibitors

A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both RatAChE and EeAChE (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Butyrylcholinesterase; Chelating Agents; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Peptide Fragments; Phthalimides; Protein Aggregates; Structure-Activity Relationship

A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Isoflavones; Mannich Bases; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship

A series of aurone Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for RatAChE, EeAChE and HuAChE (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cholinesterase Inhibitors; Drug Design; Electrophorus; Humans; Mannich Bases; Neuroprotective Agents; PC12 Cells; Rats

A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Blood-Brain Barrier; Chalcones; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Rivastigmine; Structure-Activity Relationship; Swine

Considering the complex etiology of Alzheimer's disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL-3-n-butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases. Among them, compounds 9a-d exhibited good inhibition of self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Antipyrine; Benzofurans; Binding Sites; Blood-Brain Barrier; Edaravone; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Binding; Protein Structure, Tertiary

A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cell Line; Cholinesterase Inhibitors; Humans; Kinetics; Models, Molecular; Monoamine Oxidase Inhibitors; Thioxanthenes; Xanthones

A series of 2-arylethenyl-N-methylquinolinium derivatives were designed and synthesized based on our previous research of 2-arylethenylquinoline analogues as multifunctional agents for the treatment of Alzheimer's disease (AD) (Eur. J. Med. Chem. 2015, 89, 349-361). The results of in vitro biological activity evaluation, including β-amyloid (Aβ) aggregation inhibition, cholinesterase inhibition, and antioxidant activity, showed that introduction of N-methyl in quinoline ring significantly improved the anti-AD potential of compounds. The optimal compound, compound a12, dramatically attenuated the cell death of glutamate-induced HT22 cells by preventing the generation of ROS and increasing the level of GSH. Most importantly, intragastric administration of a12•HAc was well tolerated at doses up to 2000 mg/kg and could traverse blood-brain barrier.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Cell Death; Cell Line; Cholinesterase Inhibitors; Drug Design; Glutathione; Humans; Quinolines; Reactive Oxygen Species

Previously, we have described N-Bz-L-Glu[NH-2-(1-benzylpiperidin-4-yl)ethyl]-O-nHex (IQM9.21, L-1) as an interesting multifunctional neuroprotective compound for the potential treatment of neurodegenerative diseases. Here, we describe new derivatives and different synthetic routes, such as chemoenzymatic and solid-phase synthesis, aiming to improve the previously described route in solution. The lipase-catalysed amidation of L- and D-Glu diesters with N-benzyl-4-(2-aminoethyl)piperidine has been studied, using Candida antarctica and Mucor miehei lipases. In all cases, the α-amidated compound was obtained as the main product, pointing out that regioselectivity was independent of the reacting Glu enantiomer and the nature of the lipase. An efficient solid-phase route has been used to produce new donepezil-based L- and D-Glu derivatives, resulting in good yield. At micromolar concentrations, the new compounds inhibited human cholinesterases and protected neurons against toxic insults related to Alzheimer's disease and cerebral ischemia. The CNS-permeable compounds N-Cbz-L-Glu(OEt)-[NH-2-(1-benzylpiperidin-4-yl)ethyl] (L-3) and L-1 blocked the voltage-dependent calcium channels and L-3 protected rat hippocampal slices against oxygen-glucose deprivation, becoming promising anti-Alzheimer and anti-stroke lead compounds.

Topics: Alzheimer Disease; Animals; Brain Ischemia; Calcium Channel Blockers; Cholinesterase Inhibitors; Donepezil; Glutamates; Hippocampus; Humans; Indans; Neuroprotective Agents; Piperidines; Rats; Solid-Phase Synthesis Techniques

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Coumaric Acids; Drug Design; Eels; Humans; Memory Disorders; Mice; PC12 Cells; Rats

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Electrophorus; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Quinolines; Swine

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-β (Aβ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Coumarins; Dose-Response Relationship, Drug; Drug Design; Humans; Male; Mice; Mice, Inbred Strains; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Pargyline; PC12 Cells; Protein Aggregates; Rats; Structure-Activity Relationship

Combining N-benzyl pyridinium moiety and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activities were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for ChE and Aβ (1-42) self-aggregation, and clearly selective inhibition to MAO-B over MAO-A. Of these compounds, compound 7f was the most potent inhibitor for hMAO-B, and it was also a good and balanced inhibitor to ChEs and hMAO-B (0.0373 μM for eeAChE; 2.32 μM for eqBuChE; 1.57 μM for hMAO-B). Molecular modeling and kinetic studies revealed that compound 7f was a mixed-type inhibitor, which bond simultaneously to CAS and PAS of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, compound 7f with no toxicity on PC12 neuroblastoma cells, showed good ability to inhibit Aβ (1-42) self-aggregation and cross the BBB. Collectively, all these results suggested that compound 7f might be a promising multi-target lead candidate worthy of further pursuit.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cholinesterase Inhibitors; Coumarins; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Protein Aggregates; Pyridinium Compounds; Rats; Structure-Activity Relationship

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

Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. In recent years, a plethora of proteins and biochemical pathways has been proposed as possible targets to counteract neurotoxicity. Although the complex scenario is not completely elucidated, close relationships are emerging among some of these actors. In particular, increasing evidence has shown that aggregation of amyloid beta (Aβ), glycogen synthase kinase 3β (GSK-3β) and oxidative stress are strictly interconnected and their concomitant modulation may have a positive and synergic effect in contrasting AD-related impairments. We designed compound 3 which demonstrated the ability to inhibit both GSK-3β (IC

Topics: Alzheimer Disease; Animals; Cinnamates; Dose-Response Relationship, Drug; Free Radical Scavengers; Glycogen Synthase Kinase 3 beta; Molecular Structure; Stereoisomerism; Structure-Activity Relationship

A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-β (Aβ) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Dose-Response Relationship, Drug; Drug Design; Humans; Hydrogen Peroxide; Imines; Ligands; Lipopolysaccharides; Mice; Microglia; Molecular Docking Simulation; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Peptide Fragments; Protein Aggregates; Rats; Salicylates; Structure-Activity Relationship

A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC

Topics: Alzheimer Disease; Amines; Binding Sites; Blood-Brain Barrier; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Cholinesterases; Drug Design; Humans; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Phthalimides; Protein Structure, Tertiary; Structure-Activity Relationship

A series of 2-acetyl-5-O-(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimer's disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency (eeAChE, IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Benzophenones; Binding Sites; Blood-Brain Barrier; Cell Survival; Cholinesterase Inhibitors; Drug Design; Humans; Hydrogen Peroxide; Inhibitory Concentration 50; Molecular Docking Simulation; Monoamine Oxidase; Neuroprotective Agents; PC12 Cells; Permeability; Phenols; Piperazines; Protein Structure, Tertiary; Rats; Structure-Activity Relationship

Combining N-benzylpiperidine moiety of donepezil and coumarin into in a single molecule, novel hybrids with ChE and MAO-B inhibitory activity were designed and synthesized. The biological screening results indicated that most of compounds displayed potent inhibitory activity for AChE and BuChE, and clearly selective inhibition to MAO-B. Of these compounds, 5m was the most potent inhibitor for eeAChE and eqBuChE (0.87 μM and 0.93 μM, respectively), and it was also a good and balanced inhibitor to hChEs and hMAO-B (1.37 μM for hAChE; 1.98 μM for hBuChE; 2.62 μM for hMAO-B). Molecular modeling and kinetic studies revealed that 5m was a mixed-type inhibitor, which bond simultaneously to CAS, PAS and mid-gorge site of AChE, and it was also a competitive inhibitor, which occupied the active site of MAO-B. In addition, 5m showed good ability to cross the BBB and had no toxicity on SH-SY5Y neuroblastoma cells. Collectively, all these results suggested that 5m might be a promising multi-target lead candidate worthy of further pursuit.

Topics: Alzheimer Disease; Animals; Butyrylcholinesterase; Cell Line, Tumor; Cholinesterase Inhibitors; Cholinesterases; Coumarins; Donepezil; Dose-Response Relationship, Drug; Drug Design; Eels; Humans; Indans; Models, Molecular; Molecular Structure; Molecular Targeted Therapy; Piperidines; Structure-Activity Relationship

A novel series of ferulic acid-memoquin hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro studies showed that most of the compounds exhibited a significant ability to inhibit acetylcholinesterase (AChE) (IC50 of 3.2-34.7μM) and self-induced β-amyloid (Aβ1-42) aggregation (30.8-39.1%, 25μM), to act as potential antioxidants (ORAC-FL value of 0.9-1.3). In particular, compound 17d had the greatest ability to inhibit AChE (IC50=3.2μM), and Aβ1-42 aggregation (30.8%) was also an excellent antioxidant and neuroprotectant. Moreover, it is capable of disaggregating self-induced Aβ aggregation. Furthermore, 17d could cross the blood-brain barrier (BBB) in vitro. The results showed that compound 17d is a potential multifunctional agent for the treatment of AD.

Topics: Alkanes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Chemistry Techniques, Synthetic; Cholinesterase Inhibitors; Coumaric Acids; Drug Design; Drug Evaluation, Preclinical; Ethylamines; Humans; Hydrogen Peroxide; Neuroprotective Agents; PC12 Cells; Rats

A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu(2+)-induced Aβ1-42 aggregation with 99.2% and 84.0% at 25μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC50 values of 0.271μM and 0.393μM, respectively. However the 6-methoxyl aurones 15a-c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood-brain barrier (BBB) permeabilities in vitro.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzofurans; Blood-Brain Barrier; Chelating Agents; Copper; Humans; Models, Molecular; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Peptide Fragments; Protein Aggregates; Swine

Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

Topics: 3-Hydroxyacyl CoA Dehydrogenases; Alzheimer Disease; Animals; Benzothiazoles; Cell Survival; CHO Cells; Cricetulus; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Humans; Molecular Structure; Structure-Activity Relationship; Urea

A novel series of compounds obtained by fusing the acetylcholinesterase (AChE) inhibitor donepezil and the antioxidant melatonin were designed as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (eqBuChE and hBuChE), and β-amyloid (Aβ) aggregation, and to act as potential antioxidants and biometal chelators. Especially, 4u displayed a good inhibition of AChE (IC50 value of 193nM for eeAChE and 273nM for hAChE), strong inhibition of BuChE (IC50 value of 73nM for eqBuChE and 56nM for hBuChE), moderate inhibition of Aβ aggregation (56.3% at 20μM) and good antioxidant activity (3.28trolox equivalent by ORAC assay). Molecular modeling studies in combination with kinetic analysis revealed that 4u was a mixed-type inhibitor, binding simultaneously to catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 4u could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results strongly indicated the hybridization approach is an efficient strategy to identify novel scaffolds with desired bioactivities, and further optimization of 4u may be helpful to develop more potent lead compound for AD treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Catalytic Domain; Cell Line, Tumor; Chelating Agents; Cholinesterase Inhibitors; Donepezil; Electrophorus; Horses; Humans; Indans; Indoles; Iron; Kinetics; Melatonin; Molecular Docking Simulation; Peptide Fragments; Piperidines; Protein Multimerization; Rats; Zinc

A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aβ interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aβ1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aβ1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Cell Survival; Cholinesterase Inhibitors; Copper; Donepezil; Drug Design; Humans; Indans; Kinetics; Liver; Mice; Models, Molecular; Peptide Fragments; Piperidines; Protein Aggregates; Protein Conformation

A series of coumarin derivatives were designed, synthesized, and evaluated as novel multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most of these compounds exhibited significant potency to inhibit hMAO-B selectively and self-induced Aβ1-42 aggregation. In particular, compound 13 presented the greatest potential to inhibit hMAO-B (IC50=0.081μM, SI >1234) and good inhibition of Aβ1-42 aggregation (52.9% at 20μM). Moreover, compound 13 could function as a metal-chelator, penetrate the blood-brain barrier (BBB) and show low cell toxicity in rat pheochromocytoma (PC12) and SH-SY5Y cells. Taken together, these results suggested that compound 13 might be a promising multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Binding Sites; Blood-Brain Barrier; Cell Line, Tumor; Cell Survival; Chelating Agents; Coumarins; Drug Design; Humans; Metals; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; PC12 Cells; Protein Structure, Tertiary; Rats

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

Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Animals; Antioxidants; Biphenyl Compounds; Blood-Brain Barrier; Cell Survival; Chemical and Drug Induced Liver Injury; Cholinesterase Inhibitors; Chromans; Drug Design; In Vitro Techniques; Kinetics; Male; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; PC12 Cells; Picrates; Rats; Swine; Tacrine

A series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as multi-target agents against Alzheimer's disease. The biological assays indicated that most of compounds displayed potent inhibitory activity toward AChE and BuChE, and clearly selective inhibition for MAO-B. Among these compounds, 14c exhibited strong inhibitory activity for AChE (IC50 values of 33.63 nM for eeAChE and 16.11 nM for hAChE) and BuChE (IC50 values of 80.72 nM for eqBuChE and 112.72 nM for hBuChE), and the highest inhibitory activity against hMAO-B (IC50 value of 0.24 μM). Kinetic and molecular modeling studies revealed that 14c was a mixed-type inhibitor, binding simultaneously to catalytic, peripheral and mid-gorge sites of AChE. It was also a competitive inhibitor, which covered the substrate and entrance cavities of MAO-B. Moreover, 14c could penetrate the CNS and show low cell toxicity. Overall, these results suggested that 14c might be an excellent multi-target agent for AD treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Benzopyrans; Blood-Brain Barrier; Brain; Cell Survival; Cells, Cultured; Cholinesterase Inhibitors; Coumarins; Drug Design; Erythrocytes; Humans; Kinetics; Models, Molecular; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neuroblastoma; Piperazines; Tacrine

Alzheimer's disease is the most common cause of dementia. Currently, acetylcholinesterase (AChE) inhibition is the most widely used therapeutic treatment. A large number of naturally occurring compounds have been found to inhibit AChE. In this report the mechanism of AChE inhibition of two Amaryllidaceae alkaloids, 8-O-demethylmaritidine (1) and undulatine (2), and their possible penetration across the blood-brain barrier have been studied. Both compounds act via a mixed inhibition mechanism. Based on the parallel artificial permeation assay (PAMPA) for the prediction of blood-brain barrier (BBB) penetration, only 2 should be able to cross the BBB by passive permeation.

Topics: Acetylcholinesterase; Alzheimer Disease; Amaryllidaceae Alkaloids; Biological Transport; Blood-Brain Barrier; Cholinesterase Inhibitors; Humans; In Vitro Techniques; Molecular Structure

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cholinesterase Inhibitors; Cholinesterases; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Naphthyridines; Structure-Activity Relationship; Tacrine; tau Proteins; Tauopathies

A series of indanone derivatives were designed, synthesized, and tested using a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations assessed the activities of the agents for the inhibition of cholinesterases (AChE and BuChE), the inhibition of amyloid beta (Aβ) self-assembly, and the catalysis of the disassembly of preformed Aβ oligomers and measured their antioxidant activities. Our results demonstrate that most of the synthesized compounds demonstrated good inhibitory activity against AChE with IC50 values in the nanomolar range. In particular, compounds 9 (IC50 = 14.8 nM) and 14 (IC50 = 18.6 nM) exhibited markedly higher inhibitory activities than tacrine and similar activities to donepezil. In addition, 9 and 14 significantly inhibited Aβ aggregation (inhibition rates of 85.5% and 83.8%, respectively), catalysed the disaggregation of Aβ fibrils generated by self-induced Aβ aggregation, and exhibited antioxidant activity. Furthermore, these two compounds can cross the blood-brain barrier (BBB) in vitro. These properties highlight the potential of these new compounds to be developed as multi-functional drugs for the treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Humans; Indans; Inhibitory Concentration 50; Ligands; Peptide Fragments; Permeability; Protein Aggregates

A series of tacrine-(β-carboline) hybrids (11a-q) were designed, synthesized and evaluated as multifunctional cholinesterase inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of them exhibited significant potency to inhibit acetylcholinesterase (eeAChE and hAChE), butyrylcholinesterase (BuChE) and self-induced β-amyloid (Aβ) aggregation, Cu(2+)-induced Aβ (1-42) aggregation, and to chelate metal ions. Especially, 11 l presented the greatest ability to inhibit cholinesterase (IC50, 21.6 nM for eeAChE, 63.2 nM for hAChE and 39.8 nM for BuChE), good inhibition of Aβ aggregation (65.8% at 20 μM) and good antioxidant activity (1.57 trolox equivalents). Kinetic and molecular modeling studies indicated that 11 l was a mixed-type inhibitor, binding simultaneously to the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. In addition, 11 l could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). These results suggested that 11 l might be an excellent multifunctional agent for AD treatment.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Blood-Brain Barrier; Butyrylcholinesterase; Carbolines; Cell Line; Chelating Agents; Cholinesterase Inhibitors; Drug Design; Electrophorus; Horses; Humans; Molecular Docking Simulation; Protein Aggregation, Pathological; Tacrine

A series of Tacrine-Homoisoflavonoid hybrids were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and human monoamine oxidases (MAOs). Most of the compounds were found to be potent against both ChEs and MAO-B. Among these hybrids, compound 8b, with a 6 carbon linker between tacrine and (E)-7-hydroxy-3-(4-methoxybenzylidene)chroman-4-one, proved to be the most potent against AChE and MAO-B with IC50 values of 67.9 nM and 0.401 μM, respectively. This compound was observed to cross the blood-brain barrier (BBB) in a parallel artificial membrane permeation assay for the BBB (PAMPA-BBB). The results indicated that compound 8b is an excellent multifunctional promising compound for development of novel drugs for Alzheimer's disease (AD).

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Cholinesterase Inhibitors; Cholinesterases; Electrophorus; Humans; Isoflavones; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Swine; Tacrine

In this work, we report a rational structure-based approach aimed at the discovery of new 2-aminoimidazoles as β-secretase inhibitors. Taking advantage of a microwave-assisted synthetic protocol, a small library of derivatives was obtained and biologically evaluated. Two compounds showed promising activities in both enzymatic and cellular assays. Moreover, one of them exhibited the capability to cross the blood-brain barrier as assessed by the parallel artificial membrane permeability assay.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Cell Survival; Chickens; Humans; Imidazoles; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Models, Molecular; Neurons; Small Molecule Libraries; Spectrometry, Mass, Electrospray Ionization; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship

We have previously reported the multifunctional profile of N-(3-chloro-10H-phenothiazin-10-yl)-3-(dimethylamino)propanamide (1) as an effective neuroprotectant and selective butyrylcholinesterase inhibitor. In this paper, we have developed a series of N-acylaminophenothiazines obtained from our compound library or newly synthesised. At micro- and sub-micromolar concentrations, these compounds selectively inhibited butyrylcholinesterase (BuChE), protected neurons against damage caused by both exogenous and mitochondrial free radicals, showed low toxicity, and could penetrate into the CNS. In addition, N-(3-chloro-10H-phenothiazin-10-yl)-2-(pyrrolidin-1-yl)acetamide (11) modulated the cytosolic calcium concentration and protected human neuroblastoma cells against several toxics, such as calcium overload induced by an L-type Ca2+-channel agonist, tau-hyperphosphorylation induced by okadaic acid and Aβ peptide.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antineoplastic Agents; Butyrylcholinesterase; Calcium; Cell Death; Cell Survival; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Molecular Structure; Okadaic Acid; Peptide Fragments; Phenothiazines; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured

Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC(50) 105 +/- 15 nM) is associated to a 30.7 +/- 8.6% inhibition of the proaggregating action of AChE on the Abeta and a moderate inhibition of Abeta self-aggregation (34.9 +/- 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca(2+) channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Butyrylcholinesterase; Calcium; Calcium Channel Blockers; Catalytic Domain; Cell Death; Cell Line, Tumor; Cholinesterase Inhibitors; Cytosol; Dihydropyridines; Humans; Hydrogen Peroxide; Kinetics; Ligands; Models, Molecular; Peptide Fragments; Permeability; Tacrine

Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Binding Sites; Blood-Brain Barrier; Butyrylcholinesterase; Cattle; Cholinesterase Inhibitors; Drug Design; Humans; Isomerism; Membranes, Artificial; Mice; Models, Molecular; Molecular Conformation; Permeability; Protein Binding; Tacrine

Novel multifunctional compounds have been designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease (AD). With an L-glutamic moiety as a suitable biocompatible linker, three pharmacophoric groups were joined: (1) an N-benzylpiperidine fragment selected to inhibit acetylcholinesterase by interacting with the catalytic active site (CAS), (2) an N-protecting group of the amino acid, capable of interacting with the acetylcholinesterase (AChE)-peripheral anionic site (PAS) and protecting neurons against oxidative stress, and (3) a lipophilic alkyl ester that would facilitate penetration into the central nervous system by crossing the blood-brain barrier. At submicromolar concentration, they inhibit AChE and butyrylcholinesterase (BuChE) of human origin, displace the binding of propidium iodide from the PAS of AChE, and could thus inhibit Abeta aggregation promoted by AChE. They also display neuroprotective properties against mitochondrial free radicals, show low toxicity, and could be able to penetrate into the CNS.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Catalytic Domain; Cattle; Cell Death; Cell Line, Tumor; Cell Survival; Cholinergic Agents; Cholinesterase Inhibitors; Esters; Glutamic Acid; Humans; Hydrophobic and Hydrophilic Interactions; Neuroprotective Agents; Permeability; Piperidines; Protein Binding