memoquin and Alzheimer-Disease

Alzheimer's disease is a chronic and progressive brain neurodegenerative disease affecting over 30 million people globally. Currently, no effective treatment is available due to multiple factors involved in the progression of AD. Given that the numerous AD-related targets in the disease network, the multi-target-directed ligands (MTDLs) strategy are considered as the promising strategy to treat AD. Herein, the multi-target compounds with/without ChEs are in clinical and in progress are reviewed. To further characterize the drug-likeness, and ADME properties are calculated using the Qikprop. This review will provide highlights for the treatment of AD.

Topics: Alzheimer Disease; Cholinesterase Inhibitors; Humans; Ligands; Neurodegenerative Diseases

Multitarget agents directed at selected molecular targets involved in the pathogenic cascade of Alzheimer's disease (AD) have been increasingly sought after in recent years, with the aim of achieving enhanced therapeutic efficiency with respect to single-target drugs and drug candidates. At the same time, much attention has been devoted to identifying high quality pharmacological tools to help explore the molecular mechanisms underlying AD without being exposed to physicochemical challenges. Herein, we discuss several examples of both types of compounds, taken from our own research and derived from the leads memoquin, lipocrine and bis(7)tacrine.

Topics: Acetylcholinesterase; Alkanes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Enzyme Inhibitors; Ethylamines; Humans; Ligands; Tacrine; Thioctic Acid

Alzheimer's disease is currently thought to be a complex, multifactorial syndrome, unlikely to arise from a single causal factor; instead, a number of related biological alterations are thought to contribute to its pathogenesis. This may explain why the currently available drugs, developed according to the classic drug discovery paradigm of "one-molecule-one-target," have turned out to be palliative. In light of this, drug combinations that can act at different levels of the neurotoxic cascade offer new avenues toward curing Alzheimer's and other neurodegenerative diseases. In parallel, a new strategy is emerging-that of developing a single chemical entity able to modulate multiple targets simultaneously. This has led to a new paradigm in medicinal chemistry, the "multi-target-directed ligand" design strategy, which has already been successfully exploited at both academic and industrial levels. As a case study, we report here on memoquin, a new molecule developed following this strategy. The in vitro and in vivo biological profile of memoquin demonstrates the suitability of the new strategy for obtaining innovative drug candidates for the treatment of neurodegenerative diseases.

Topics: Alkanes; Alzheimer Disease; Amides; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Anisoles; Antioxidants; Aspartic Acid Endopeptidases; Attention; Choline; Drug Design; Ethylamines; Galantamine; Humans; Memory; Neurons; Phosphorylation; Plaque, Amyloid; Platelet Aggregation Inhibitors; tau Proteins

The multifunctional nature of Alzheimer's disease (AD) provides the logical foundation for the development of an innovative drug design strategy centered on multi-target-directed-ligands (MTDLs). In recent years, the MTDL concept has been exploited to design different ligands hitting different biological targets. Our first rationally designed MTDL was the polyamine caproctamine (1), which provided a synergistic cholinergic action against AD by antagonizing muscarinic M(2) autoreceptors and inhibiting acetylcholinesterase (AChE). Lipocrine (7) represented the next step in our research. Due to its ability to inhibit AChE catalytic and non-catalytic functions together with oxidative stress, 7 emerged as an interesting pharmacological tool for investigating the neurodegenerative mechanism underlying AD. Memoquin (9) is a quinone-bearing polyamine endowed with a unique multifunctional profile. With its development, we arrived at the proof of concept of the MTDL drug discovery approach. Experiments in vitro and in vivo confirmed its multimodal mechanisms of action and its interaction with different end-points of the neurotoxic cascade leading to AD. More recently, the MTDL approach led to carbacrine (12). In addition to the multiple activities displayed by 7, 12 displayed an interesting modulation of NMDA receptor activity. The pivotal role played by this target in AD pathogenesis suggests that 12 may be a promising new chemical entity in the MTDL gold rush.

Topics: Alkanes; Alzheimer Disease; Animals; Carbazoles; Cholinesterase Inhibitors; Drug Delivery Systems; Drug Design; Ethylamines; Humans; Ligands; Tacrine; Thioctic Acid

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

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

Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and β-amyloid self-aggregation. Selected compounds displayed significant inhibition of human β-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both β-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 μM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Behavior, Animal; Benzofurans; Cell Line; Cell Survival; Chemical and Drug Induced Liver Injury; Cholinesterase Inhibitors; Crystallography, X-Ray; Drug Design; Humans; Male; Mice; Mice, Inbred ICR; Models, Molecular; Nootropic Agents; Structure-Activity Relationship; Tacrine; Torpedo

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

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, and BACE-1, dual Aβ42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction, preventing the loss of synaptic proteins and/or have a positive effect on the induction of long-term potentiation. In vivo studies in APP-PS1 transgenic mice treated ip for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Anthraquinones; Aspartic Acid Endopeptidases; Binding Sites; Blood-Brain Barrier; Cholinesterase Inhibitors; Enzyme Inhibitors; Escherichia coli; Hippocampus; Humans; In Vitro Techniques; Kinetics; Long-Term Potentiation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Molecular; Peptide Fragments; Stereoisomerism; Synapses; tau Proteins

The anti-amyloid properties shared by several quinones inspired the design of a new series of hybrids derived from the multi-target drug candidate memoquin (1). The hybrids consist of a central benzoquinone core and a fragment taken from non-steroidal anti-inflammatory drugs, connected through polyamine linkers. The new hybrids retain the potent anti-aggregating activity of the parent 1, while exhibiting micromolar AChE inhibitory activities. Remarkably, 2, 4, (R)-6 and (S)-6 were Aβ aggregation inhibitors even more potent than 1. The balanced amyloid/cholinesterase inhibitory profile is an added value that makes the present series of compounds promising leads against Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cholinesterase Inhibitors; Humans; Ligands; Mice; Models, Molecular; Protein Binding; Quinones; Structure-Activity Relationship

Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and β-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aβ-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aβ-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aβ-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.

Topics: Alkanes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Disease Models, Animal; Ethylamines; Female; Male; Maze Learning; Memory; Mice; Motor Activity; Neurons; Neuroprotective Agents; Rats

Memoquin (1) is a lead compound multitargeted against Alzheimer's disease (AD). It is an AChE inhibitor, free-radical scavenger, and inhibitor of amyloid-β (Aβ) aggregation. A new series of 1 derivatives was designed and synthesized by linking its 2,5-diamino-benzoquinone core with motifs that are present in the structure of known amyloid binding agents like curcumin, the benzofuran derivative SKF64346, or the benzothiazole bearing compounds KHG21834 and BTA-1. The weaker AChE inhibitory potencies and the concomitant nearly equipotent anti-amyloid activities of the new compounds with respect to 1 resulted in a more balanced biological profile against both targets. Selected compounds turned out to be effective Aβ aggregation inhibitors in a cell-based assay. By properly combining two or more distinct pharmacological properties in a molecule, we can achieve greater effectiveness compared to single-targeted drugs for investigating AD.

Topics: Alkanes; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Cells, Cultured; Cholinesterase Inhibitors; Drug Delivery Systems; Drug Discovery; Enzyme Inhibitors; Ethylamines; Humans; Inhibitory Concentration 50; Molecular Structure

Lipoic acid (LA) is a natural antioxidant. Its structure was previously combined with that of the acetylcholinesterase inhibitor tacrine to give lipocrine (1), a lead compound multitargeted against Alzheimer's disease (AD). Herein, we further explore LA as a privileged structure for developing multimodal compounds to investigate AD. First, we studied the effect of LA chirality by evaluating the cholinesterase profile of 1's enantiomers. Then, a new series of LA hybrids was designed and synthesized by combining racemic LA with motifs of other known anticholinesterase agents (rivastigmine and memoquin). This afforded 4, which represents a step forward in the search for balanced anticholinesterase and antioxidant capacities.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Butyrylcholinesterase; Cell Line; Cholinesterase Inhibitors; Drug Discovery; Humans; Ligands; Peptide Fragments; Protein Multimerization; Protein Structure, Secondary; Thioctic Acid

The present article expands on the study of structure-activity relationships of the novel class of quinone-bearing polyamines, as multi-target-directed ligands against Alzheimer's disease. Namely, the effect of inserting a methyl substituent at the alpha position of the terminal benzyl amine moieties of lead candidate 1 (memoquin) was evaluated at the multiple targets involved in the multifunctional mechanism of action. The RR stereoisomer 2 resulted more effective than 1 in reverting two important effects mediated by acetylcholinesterase (AChE), that is, acetylcholine hydrolysis and AChE-induced amyloid-beta aggregation.

Topics: Acetylcholinesterase; Alkanes; Alzheimer Disease; Amines; Amyloid beta-Peptides; Animals; Dose-Response Relationship, Drug; Ethylamines; Humans; Hydrolysis; Inhibitory Concentration 50; Mice; Models, Chemical; Polyamines; Quinones; Stereoisomerism; Structure-Activity Relationship

Novel multitargeted antioxidants 3-6 were designed by combining the antioxidant features, namely, a benzoquinone fragment and a lipoyl function, of two multifunctional lead candidates. They were then evaluated to determine their profile against Alzheimer's disease. They showed antioxidant activity, improved following enzymatic reduction, in mitochondria and T67 cell line. They also displayed a balanced inhibitory profile against amyloid-beta aggregation and acetylcholinesterase, emerging as promising molecules for neuroprotectant lead discovery.

Topics: Alkanes; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Cell Line, Tumor; Drug Design; Electron Transport; Ethylamines; Humans; Ligands; Protein Binding; Reactive Oxygen Species; Submitochondrial Particles; Thioctic Acid; Ubiquinone

The photostability properties of memoquin, a multifunctional compound in preclinical development for the treatment of Alzheimer's disease (AD) were investigated in solutions exposed to radiations, using a xenon arc lamp to simulate the natural sunlight. Reversed phase liquid chromatography coupled with diode array detection and electrospray ionization mass spectrometry (LC-UV/DAD-ESI-MS/MS) was applied to follow the photodegradation and disappearance of memoquin after irradiation. Under optimized chromatographic conditions, memoquin was separated with high resolution from the photoproducts formed in the photoexposed solutions. The results showed that memoquin is more stable at physiological and acid pHs, while it has a slow degradation pattern at more drastic conditions such as basic pH (t(1/2)=389 min) and in methanolic solutions (t(1/2)=465 min). In the irradiated solutions the appearance of photoproducts with lower retention times and molecular weight than memoquin was observed, thus indicating that some fragments were lost from its structure. The photodegradation products were characterized by LC-ESI-MS/MS and LC-UV/DAD analysis. The photoreactive centers were found on the amino groups of the side chains while the 1,4-benzoquinone functionality was maintained. Conversely, memoquin was found to be stable in the dark. These results suggest that, with appropriate handling and storage, memoquin's activity is not impaired.

Topics: Alkanes; Alzheimer Disease; Chromatography, Liquid; Drug Stability; Ethylamines; Light; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet; Tandem Mass Spectrometry

One of the characteristics of Alzheimer's disease (AD) that hinders the discovery of effective disease-modifying therapies is the multifactorial nature of its etiopathology. To circumvent this drawback, the use of multi-target-directed ligands (MTDLs) has recently been proposed as a means of simultaneously hitting several targets involved in the development of the AD syndrome. In this paper, a new class of MTDLs based on a polyamine-quinone skeleton, whose lead (memoquin, 2) showed promising properties in preclinical investigations (Cavalli et al. Angew. Chem., Int. Ed. 2007, 46, 3689-3692), is described. 3-29 were tested in vitro against a number of isolated AD-related targets, namely, AChE and BChE, and Abeta aggregation (both AChE-mediated and self-induced). Furthermore, the ability of the compounds to counteract the oxidative stress in a human neuronal-like cellular system (SH-SY5Y cells) was assayed, in both the presence and absence of NQO1, an enzyme able to generate and maintain the reduced form of quinone.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Binding Sites; Butyrylcholinesterase; Cell Line; Cholinesterase Inhibitors; Humans; Ligands; Models, Molecular; NAD(P)H Dehydrogenase (Quinone); Oxidative Stress; Polyamines; Protein Binding; Quinones; Reactive Oxygen Species; Structure-Activity Relationship; Substrate Specificity

Topics: Alkanes; Alzheimer Disease; Animals; Disease Models, Animal; Drug Delivery Systems; Drug Evaluation, Preclinical; Ethylamines; Humans; Mice; Mice, Transgenic; Models, Molecular; Molecular Structure; Stereoisomerism; Structure-Activity Relationship