ABSTRACT
Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 µM) with pyrimidone compound 5 (GSK-3ß: IC50 = 3 µM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3ß (GSK-3ß). The optimal compound 18a possessed potent dual AChE/GSK-3ß inhibition (AChE: IC50 = 0.047 ± 0.002 µM, GSK-3ß: IC50 = 0.930 ± 0.080 µM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 µM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.
Subject(s)
Acetylcholinesterase , Alzheimer Disease , Cholinesterase Inhibitors , Drug Design , Glycogen Synthase Kinase 3 beta , Molecular Docking Simulation , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Humans , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Acetylcholinesterase/metabolism , Acetylcholinesterase/chemistry , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta/metabolism , Cell Line, Tumor , Sulfur/chemistry , Structure-Activity Relationship , Acridines/chemistry , Acridines/pharmacology , Acridines/chemical synthesis , Tacrine/chemistry , Tacrine/pharmacology , Tacrine/chemical synthesis , Molecular StructureABSTRACT
The synthesis of four tetra-tacrine clusters where the tacrine binding units are attached to a central scaffold via linkers of variable lengths is described. The multivalent inhibition potencies for the tacrine clusters were investigated for the inhibition of acetylcholinesterase. Two of the tacrine clusters displayed a small but significant multivalent inhibition potency in which the binding affinity of each of the tacrine binding units increased up to 3.2 times when they are connected to the central scaffold.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Drug Development , Tacrine/pharmacology , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Electrophorus , Molecular Structure , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
We have used the Cu(i)-catalyzed azide-alkyne Huisgen cycloaddition reaction to obtain two families of bivalent heterodimers where tacrine is connected to an azasugar or iminosugar, respectively, via linkers of variable length. The heterodimers were investigated as cholinesterase inhibitors and it was found that their activity increased with the length of the linker. Two of the heterodimers were significantly stronger acetylcholinesterase inhibitors than the monomeric tacrine. Molecular modelling indicated that the longer heterodimers fitted better into the active gorge of acetylcholinesterase than the shorter counterparts and the former provided more efficient simultaneous interaction with the tryptophan residues in the catalytic anionic binding site (CAS) and the peripheral anionic binding site (PAS).
Subject(s)
Cholinesterase Inhibitors/chemistry , Imino Sugars/chemistry , Tacrine/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Animals , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Electrophorus , Enzyme Assays , Horses , Imino Sugars/chemical synthesis , Imino Sugars/metabolism , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/metabolism , ThermodynamicsABSTRACT
Alzheimer's disease (AD) is one of the most common types of dementia, especially in elderly, with an increasing number of people suffering from this disease worldwide. There are no available disease-modifying therapies and only four drugs are approved for the relief of symptoms. Currently, the therapeutic approach used for AD treatment is based on single target drugs, which are not capable to stop its progression. To address this issue, multi-target compounds, combining two or more pharmacophores in a single molecular entity, have gained increasing interest to deal with the multiple factors related to AD. The exact cause of AD is not yet completely disclosed, and several hallmarks have been associated to this neurodegenerative disease. Even though, the accumulation of both amyloid-ß plaques (Aß) and neurofibrillary tangles (NFTs) are fully accepted as the main AD hallmarks, being object of lots of research for early-stage diagnosis and pharmacological therapy. In this context, this review summarizes the state-of-the-art in the field of dual-target inhibitors of both Aß and tau aggregation simultaneously, including the design and synthetic strategy of the dual-target compounds, as well as a brief structure-activity relationships (SAR) analysis.
Subject(s)
Alzheimer Disease/drug therapy , Aminoquinolines/pharmacology , Amyloid beta-Peptides/antagonists & inhibitors , Curcumin/pharmacology , Heterocyclic Compounds, 4 or More Rings/pharmacology , Tacrine/pharmacology , tau Proteins/antagonists & inhibitors , Alzheimer Disease/metabolism , Aminoquinolines/chemical synthesis , Aminoquinolines/chemistry , Amyloid beta-Peptides/metabolism , Curcumin/chemical synthesis , Curcumin/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistry , tau Proteins/metabolismABSTRACT
In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC50 values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors (5e and 5d) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta (ßA) aggregation and ß-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Pyridines/pharmacology , Tacrine/pharmacology , Acetylcholinesterase/drug effects , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Butyrylcholinesterase/drug effects , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Pyridines/chemical synthesis , Pyridines/chemistry , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
We synthesized a set of new hybrid derivatives (7-C8, 7-C10, 7-C12 and 8-C8, 8-C10, 8-C12), in which a polymethylene spacer chain of variable length connected the pharmacophoric moiety of xanomeline, an M1/M4-preferring orthosteric muscarinic agonist, with that of tacrine, a well-known acetylcholinesterase (AChE) inhibitor able to allosterically modulate muscarinic acetylcholine receptors (mAChRs). When tested in vitro in a colorimetric assay for their ability to inhibit AChE, the new compounds showed higher or similar potency compared to that of tacrine. Docking analyses were performed on the most potent inhibitors in the series (8-C8, 8-C10, 8-C12) to rationalize their experimental inhibitory power against AChE. Next, we evaluated the signaling cascade at M1 mAChRs by exploring the interaction of Gαq-PLC-ß3 proteins through split luciferase assays and the myo-Inositol 1 phosphate (IP1) accumulation in cells. The results were compared with those obtained on the known derivatives 6-C7 and 6-C10, two quite potent AChE inhibitors in which tacrine is linked to iperoxo, an exceptionally potent muscarinic orthosteric activator. Interestingly, we found that 6-C7 and 6-C10 behaved as partial agonists of the M1 mAChR, at variance with hybrids 7-Cn and 8-Cn containing xanomeline as the orthosteric molecular fragment, which were all unable to activate the receptor subtype response.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Isoxazoles/pharmacology , Pyridines/pharmacology , Quaternary Ammonium Compounds/pharmacology , Receptor, Muscarinic M1/metabolism , Tacrine/pharmacology , Thiadiazoles/pharmacology , Acetylcholinesterase/metabolism , Allosteric Regulation/drug effects , Animals , CHO Cells , Cholinesterase Inhibitors/chemistry , Cricetulus , Electrophorus , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Ligands , Molecular Docking Simulation , Pyridines/chemical synthesis , Pyridines/chemistry , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/chemistry , Receptor, Muscarinic M1/agonists , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistryABSTRACT
A thermoresponsive NIPAAm-based polymer is combined with the selective acetylcholinesterase inhibitor tacrine in order to create a strict in sense on/off switch for enzymatic activity. This polymer-inhibitor conjugate inhibits AChE at room temperature and enables reactivation of AChE by heating above the cloud point of the conjugate.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Polymers/pharmacology , Tacrine/pharmacology , Temperature , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Molecular Structure , Polymers/chemical synthesis , Polymers/chemistry , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
BACKGROUND: Alzheimer's disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease. OBJECTIVE: Novel phosphorus and thiophosphorus tacrine derivatives 7-14 were designed, synthesized and their biological activity and molecular modeling was investigated as a new potential anti- Alzheimer's disease (AD) agents. METHODS: 9-Chlorotacrine was treated with propane-1,3-diamine in the presence of sodium iodide to yield N1-(1,2,3,4-tetrahydroacridin-9-yl)propane-1,3-diamine 6. Finally, it was treated with corresponding acid ester or thioester to give phosphorus or thiophosphorus tacrine derivative 7-14. All of the obtained final structures were characterized by 1H NMR, 13C NMR, 31P NMR and MS. RESULTS: The results of the docking studies showed that the newly designed phosphorus and thiophosphorus tacrine analogs, theoretically possess AChE and BChE-binding ability. Kinetic study showed that 8 and 12 in the series proved to be more potent electric eel AChE (eeAChE) and human (hAChE) inhibitors than tacrine, where 8 inhibited eeAChE three times more than the referenced drug. The highest BChE inhibition revealed 11 and 13. The most active compounds against eeAChE, hAChE and BChE showed mixed type of inhibition. CONCLUSION: All new synthesized compound exhibited lower toxicity against neuroblastoma.cell line (SH-SY5Y) in comparison with tacrine. Two analogues in the series, 7 and 9, demonstrated lack of cytotoxicity against hepatocellular cells (hepG2).
Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Tacrine/pharmacology , Alzheimer Disease/metabolism , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Electrophorus , Humans , Phosphorylation , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
Proteinaceous infectious particles causing mammalian transmissible spongiform encephalopathies or prions are being extensively studied. However due to their hazardous nature, the initial screening of potential anti-prion drugs is often made in a yeast-based screening system utilizing a well-characterized [PSI+] prion (amyloid formed by the translation termination factor Sup35p). In the [PSI+] prion screening system (white/red colony assay), the prion phenotype yields white colonies while addition of an anti-prion drug will yield red colonies. However, this system has some limitations. It is difficult to quantify the effectiveness of the anti-prion compound, the diffusion of the studied compound may affect the result, and the deficiency of glutathione in cells may prevent the formation of red pigment in cured cells. Therefore, alternative yeast prion screening systems are still needed. This article aims to present an alternative yeast-based system to evaluate anti-prion activity of chemical compounds. The method that was used is based on an artificial [LEU2+] prion created by fusing Leu2p with the prion-forming domain of Sup35p in Saccharomyces cerevisiae. Phenotypic analysis and semi-denaturating detergent agarose gel electrophoresis (SDD-AGE) confirmed the presence of the artificial [LEU2+] prion in yeast cells. This screening system verified the anti-prion activity of 3 drugs that were found to have been active in the white/red colony assay, while one compound (6-chlorotacrine) that was active in the white/red colony assay was found to be inactive in the [LEU2+] system. This new system also appears to be more sensitive than the white/red colony assay.
Subject(s)
3-Isopropylmalate Dehydrogenase/genetics , Drug Evaluation, Preclinical/methods , Prions/drug effects , Prions/genetics , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae/genetics , Escherichia coli/genetics , Guanabenz/pharmacology , Peptide Termination Factors/genetics , Phenanthridines/pharmacology , Phenotype , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Tacrine/pharmacologyABSTRACT
Alzheimer, a progressive disease, is a common term for memory loss which interferes with daily life through severe influence on cognitive abilities. Based on the cholinergic hypothesis, and Xray crystallographic determination of the structure of acetylcholinesterase (AChE) enzyme, the level of acetylcholine (ACh, an important neurotransmitter associated with memory) in the hippocampus and cortex area of the brain has a direct effect on Alzheimer. This fact encourages scientists to design and synthesize a wide range of acetylcholinesterase inhibitors (AChEIs) to control the level of ACh in the brain, keeping in view the crystallographic structure of AChE enzyme and drugs approved by the Food and Drug Administration (FDA). AChEIs have slightly diverse pharmacological properties, but all of them work by inhibiting the segregation of ACh by blocking AChE. We reviewed significant scaffolds introduced as AChEIs. In some studies, the activity against butyrylcholinesterase (BuChE) has been evaluated as well because BuChE is a similar enzyme to neuronal acetylcholinesterase and is capable of hydrolyzing ACh. In order to study AChEIs effectively, we divided them structurally into 12 classes and briefly explained effective AChEIs and compared their activities against AChE enzyme.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemistry , Drug Design , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alkaloids/chemical synthesis , Alkaloids/chemistry , Alzheimer Disease/pathology , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/therapeutic use , Donepezil/chemical synthesis , Donepezil/chemistry , Humans , Rivastigmine/chemical synthesis , Rivastigmine/chemistry , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review.
Subject(s)
Alzheimer Disease/drug therapy , Chemistry Techniques, Synthetic , Drug Design , Drug Discovery , Animals , Chemistry Techniques, Synthetic/methods , Donepezil/analogs & derivatives , Donepezil/chemical synthesis , Donepezil/pharmacology , Dopamine Agents/chemical synthesis , Dopamine Agents/chemistry , Dopamine Agents/pharmacology , Drug Discovery/methods , Humans , Indans/chemical synthesis , Indans/chemistry , Indans/pharmacology , Memantine/analogs & derivatives , Memantine/chemical synthesis , Memantine/pharmacology , Molecular Targeted Therapy , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Nootropic Agents/chemical synthesis , Nootropic Agents/chemistry , Nootropic Agents/pharmacology , Rivastigmine/analogs & derivatives , Rivastigmine/chemical synthesis , Rivastigmine/pharmacology , Tacrine/analogs & derivatives , Tacrine/chemical synthesis , Tacrine/pharmacologyABSTRACT
Design, physicochemical and biological studies of novel radioconjugates for the early diagnosis of Alzheimer's disease, based on the newly synthesized tacrine derivatives were performed. Novel tacrine analogues were labeled with technetium-99m and gallium-68. For all obtained radioconjugates ([99mTc]Tc-Hynic-(tricine)2NH(CH2)ntacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine, where nâ¯=â¯2-9 denotes the number of methylene groups CH2) the studies of physicochemical properties (lipophilicity, stability in the presence of an excess of standard amino acids cysteine or histidine, human serum and in cerebrospinal fluid) were performed. For two selected radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9Tac and [68Ga]Ga-DOTA-NH(CH2)9tacrine (characterized with the highest lipophilicity values) the biological tests (inhibition of cholinesterases action, molecular docking and biodistribution studies) have been performed. All novel radioconjugates showed high stability in biological solutions used. Both selected radioconjugates proved to be good inhibitors of cholinesterases and be able to cross the blood-brain barrier. Radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9tacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine fulfil the conditions for application in nuclear medicine. Radiopharmaceutical [68Ga]Ga-DOTA-NH(CH2)9tacrine, due to increased accuracy and improved sensitivity in PET imaging, may be better potential diagnostic tool for early diagnosis of Alzheimer's disease.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Organotechnetium Compounds/pharmacology , Radiopharmaceuticals/pharmacology , Tacrine/analogs & derivatives , Tacrine/pharmacology , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/diagnosis , Animals , Brain/metabolism , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Catalytic Domain , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Drug Stability , Gallium Radioisotopes , Humans , Male , Molecular Docking Simulation , Organotechnetium Compounds/chemical synthesis , Organotechnetium Compounds/metabolism , Protein Binding , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/metabolism , Rats, Wistar , Tacrine/chemical synthesis , Tacrine/metabolismABSTRACT
Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease. Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease. The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of Aß42, lacking neurotoxicity up to 5 µM concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound. So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs.
Subject(s)
Alzheimer Disease/drug therapy , Antineoplastic Agents/pharmacology , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Phenols/pharmacology , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Butyrylcholinesterase/metabolism , Cell Proliferation/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dimerization , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Electrophorus , Horses , Humans , Ligands , Models, Molecular , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Phenols/chemical synthesis , Phenols/chemistry , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistry , Tumor Cells, CulturedABSTRACT
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is characterized as a multi-factorial disorder with a prevalent genetic component. Due to the unknown etiology, current treatment based on acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate receptors (NMDAR) antagonist is effective only temporary. It seems that curative treatment will necessarily be complex due to the multifactorial nature of the disease. In this context, the so-called "multi-targeting" approach has been established. OBJECTIVES: The aim of this study was to develop a multi-target-directed ligand (MTDL) combining the support for the cholinergic system by inhibition of AChE and at the same time ameliorating the burden caused by glutamate excitotoxicity mediated by the NMDAR receptors. METHODS: We have applied common approaches of organic chemistry to prepare a hybrid of 6-chlorotacrine and memantine. Then, we investigated its blocking ability towards AChE and NMDRS in vitro, as well as its neuroprotective efficacy in vivo in the model of NMDA-induced lessions. We also studied cytotoxic potential of the compound and predicted the ability to cross the blood-brain barrier. RESULTS: A novel molecule formed by combination of 6-chlorotacrine and memantine proved to be a promising multipotent hybrid capable of blocking the action of AChE as well as NMDARs. The presented hybrid surpassed the AChE inhibitory activity of the parent compound 6-Cl-THA twofold. According to results it has been revealed that our novel hybrid blocks NMDARs in the same manner as memantine, potently inhibits AChE and is predicted to cross the blood-brain barrier via passive diffusion. Finally, the MTDL design strategy was indicated by in vivo results which showed that the novel 6-Cl-THA-memantine hybrid displayed a quantitatively better neuroprotective effect than the parent compound memantine. CONCLUSION: We conclude that the combination of two pharmacophores with a synergistic mechanism of action into a single molecule offers great potential for the treatment of CNS disorders associated with cognitive decline and/or excitotoxicity mediated by NMDARs.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Memantine/pharmacology , Neuroprotective Agents/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Tacrine/analogs & derivatives , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , CHO Cells , Capillary Permeability , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cricetulus , Glutamic Acid/metabolism , HEK293 Cells , Humans , Ligands , Male , Memantine/chemical synthesis , Molecular Docking Simulation , Neuroprotective Agents/chemical synthesis , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism , Tacrine/chemical synthesis , Tacrine/pharmacology , Tissue Culture TechniquesABSTRACT
In search of potent acetyl cholinesterase inhibitors with low hepatotoxicity for the treatment of Alzheimer's disease, introduction of a chloro substitution to tacrine and some of its analogs has proven to be beneficial in maintaining or potentiating the cholinesterase inhibitory activity. Furthermore, it was found to be able to reduce the hepatotoxicity of the synthesized compounds, which is the main target of the study. Accordingly, a series of new 4-(chlorophenyl)tetrahydroquinoline derivatives, was synthesized and characterized. The synthesized compounds were evaluated for their in vitro and in vivo anti-cholinesterase activity using tacrine as a reference standard. Furthermore, they were investigated for their hepatotoxicity compared to tacrine. The obtained biological results revealed that all synthesized compounds displayed equivalent or significantly higher anti-cholinesterase activity and lower hepatotoxicity in comparison to tacrine. In addition, in silico drug-likeness of the synthesized compounds were predicted and their practical logP were assessed indicating that all synthesized compounds can be considered as promising hits/leads. Furthermore, docking study of the compound showing the highest in vitro anticholinesterase activity was performed and its binding mode was compared to that of tacrine.
Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Tacrine/pharmacology , Alzheimer Disease/metabolism , Animals , Anura , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Halogenation , Humans , Liver/drug effects , Liver/metabolism , Male , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
In view of the multifactorial nature of Alzheimer's disease (AD), multitarget small molecules (MTSM) represent the most potent and attractive therapeutic strategy to design new drugs for Alzheimer's disease therapy. The new MTSM KojoTacrines (KTs) were designed and synthesized by juxtaposition of selected pharmacophoric motifs from kojic acid and tacrine. Among them, 11-amino-2-(hydroxymethyl)-12-(3-methoxyphenyl)-7,9,10,12-tetrahydropyrano [2',3':5,6] pyrano[2,3-b]quinolin-4(8H)-one (KT2d) was identified as less-hepatotoxic than tacrine, at higher concentration, a moderate, but selective human acetylcholinesterase inhibitor (IC50 = 4.52 ± 0.24 µM), as well as an antioxidant agent (TE = 4.79) showing significant neuroprotection against Aß1-40 at 3 µM and 10 µM concentrations. Consequently, KT2d is a potential new hit-ligand for AD therapy for further biological exploration.
Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Design , Humans , Models, Molecular , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
A series of new indole-3-acetic acid (IAA)-tacrine hybrids as dual acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitors were designed and prepared based on the molecular docking mode of AChE with an IAA derivative (1a), a moderate AChE inhibitor identified by screening our compound library for anti-Alzheimer's disease (AD) drug leads. The enzyme assay results revealed that some hybrids, e.g. 5d and 5e, displayed potent dual in vitro inhibitory activities against AChE/BChE with IC50 values in low nanomolar range. Molecular modeling studies in tandem with kinetic analysis suggest that these hybrids target both catalytic active site and peripheral anionic site of cholinesterase (ChE). Molecular dynamic simulations and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) calculations indicate that 5e has more potent binding affinity than hit 1a, which may explain the stronger inhibitory effect of 5e on AChE. Furthermore, their predicted pharmacokinetic properties and in vitro influences on mouse brain neural network electrical activity were discussed. Taken together, compound 5e can be highlighted as a lead compound worthy of further optimization for designing new anti-AD drugs.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Indoleacetic Acids/pharmacology , Tacrine/analogs & derivatives , Tacrine/pharmacology , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , HEK293 Cells , Hep G2 Cells , Humans , Indoleacetic Acids/chemical synthesis , Indoleacetic Acids/chemistry , Indoleacetic Acids/metabolism , Kinetics , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/chemistryABSTRACT
A new series of tacrine-coumarin hybrids linked to 1,2,3-triazole were designed, synthesized, and tested as potent dual binding site cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD). Among them, compound 8e was the most potent anti-AChE derivative (IC50â¯=â¯27â¯nM) and compound 8m displayed the best anti-BChE activity (IC50â¯=â¯6â¯nM) much more active than tacrine and donepezil as the reference drugs. Compound 8e was also evaluated for its BACE1 inhibitory activity and neuroprotectivity against PC12 cells exposed to Aß25-35 which indicated low activity. Finally, in vivo studies by Morris water maze task showed that compound 8e significantly reversed scopolamine-induced memory deficit in rats.
Subject(s)
Coumarins/therapeutic use , Neuroprotective Agents/therapeutic use , Tacrine/analogs & derivatives , Tacrine/therapeutic use , Triazoles/therapeutic use , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Animals , Butyrylcholinesterase/chemistry , Butyrylcholinesterase/metabolism , Catalytic Domain , Cell Line, Tumor , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Coumarins/chemical synthesis , Coumarins/metabolism , Coumarins/pharmacology , Humans , Male , Maze Learning/drug effects , Molecular Docking Simulation , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Nootropic Agents/chemical synthesis , Nootropic Agents/metabolism , Nootropic Agents/pharmacology , Nootropic Agents/therapeutic use , Protein Binding , Rats, Wistar , Structure-Activity Relationship , Tacrine/chemical synthesis , Tacrine/metabolism , Torpedo , Triazoles/chemical synthesis , Triazoles/metabolism , Triazoles/pharmacologyABSTRACT
A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as d-xylose, d-ribose, and d-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the d-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50â¯=â¯2.2â¯nM for AChE and 4.93â¯nM for BuChE) was the most active compound for both enzymes. The d-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (d-ribose derivative) and 6b (d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.
Subject(s)
Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Drug Design , Tacrine/analogs & derivatives , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Animals , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Galactose/analogs & derivatives , Galactose/chemical synthesis , Galactose/pharmacology , Humans , Mice , Molecular Docking Simulation , Ribose/analogs & derivatives , Ribose/chemical synthesis , Ribose/pharmacology , Structure-Activity Relationship , Tacrine/chemical synthesis , Torpedo , Xylose/analogs & derivatives , Xylose/chemical synthesis , Xylose/pharmacologyABSTRACT
First-line medical treatment against nerve agents consists of co-administration of anticholinergic agents and oxime reactivators, which reactivate inhibited AChE. Pralidoxime, a commonly used oxime reactivator, is effective against some nerve agents but not against others; thus, new oxime reactivators are needed. Novel tacrine-pyridinium hybrid reactivators in which 4-pyridinealdoxime derivatives are connected to tacrine moieties by linear carbon chains of different lengths (C2-C7) were prepared (Scheme 1, 5a-f). Their binding affinities to electric eel AChE were tested because oximes can inhibit free AChE, and the highest AChE activity (95%, 92%, and 90%) was observed at 1⯵M concentrations of the oximes (5a, 5b, and 5c, respectively). Based on their inhibitory affinities towards free AChE, 1⯵M concentrations of the oxime derivatives (5) were used to examine reactivation of paraoxon-inhibited AChE. Reactivation ability increased as the carbon linker chains lengthened (nâ¯=â¯2-5), and 5c and 5d showed remarkable reactivation ability (41%) compared to that of 2-PAM (16%) and HI-6 (4%) against paraoxon-inhibited electric eel AChE at 1⯵M concentrations. Molecular docking simulation showed that the most stable binding free energy was observed in 5c at 73.79â¯kcalâ mol-1, and the binding mode of 5c is acceptable for the oxygen atom of oximate to attack the phosphorus atom of paraoxon and reactivate paraoxon-inhibited eel AChE model structure.