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1.
J Enzyme Inhib Med Chem ; 34(1): 163-170, 2019 Dec.
Article in English | MEDLINE | ID: mdl-30482062

ABSTRACT

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/chemistry
2.
Curr Alzheimer Res ; 15(12): 1096-1105, 2018.
Article in English | MEDLINE | ID: mdl-29992880

ABSTRACT

BACKGROUND: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets. METHODS: All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman´s method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively. RESULTS: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier. CONCLUSION: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 µmol) and 7d towards hAChE (IC50 = 0.32 µmol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 µmol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 µmol). Moreover, hybrid 5d and 7c could penetrate the CNS.


Subject(s)
Blood-Brain Barrier/drug effects , Cholinesterase Inhibitors/pharmacology , Coumarins/pharmacology , Tacrine/pharmacology , Thiourea/pharmacology , Animals , Cholinesterase Inhibitors/chemistry , Coumarins/chemistry , Humans , Kinetics , Models, Molecular , Molecular Docking Simulation , Permeability/drug effects , Structure-Activity Relationship , Tacrine/chemistry , Thiourea/chemistry
3.
Drug Des Devel Ther ; 12: 505-512, 2018.
Article in English | MEDLINE | ID: mdl-29563775

ABSTRACT

BACKGROUND: Intoxication by nerve agents could be prevented by using small acetylcholinesterase inhibitors (eg, pyridostigmine) for potentially exposed personnel. However, the serious side effects of currently used drugs led to research of novel potent molecules for prophylaxis of organophosphorus intoxication. METHODS: The molecular design, molecular docking, chemical synthesis, in vitro methods (enzyme inhibition, cytotoxicity, and nicotinic receptors modulation), and in vivo methods (acute toxicity and prophylactic effect) were used to study bispyridinium, bisquinolinium, bisisoquinolinium, and pyridinium-quinolinium/isoquinolinium molecules presented in this study. RESULTS: The studied molecules showed non-competitive inhibitory ability towards human acetylcholinesterase in vitro that was further confirmed by molecular modelling studies. Several compounds were selected for further studies. First, their cytotoxicity, nicotinic receptors modulation, and acute toxicity (lethal dose for 50% of laboratory animals [LD50]; mice and rats) were tested to evaluate their safety with promising results. Furthermore, their blood levels were measured to select the appropriate time for prophylactic administration. Finally, the protective ratio of selected compounds against soman-induced toxicity was determined when selected compounds were found similarly potent or only slightly better to standard pyridostigmine. CONCLUSION: The presented small bisquaternary molecules did not show overall benefit in prophylaxis of soman-induced in vivo toxicity.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Nerve Agents/adverse effects , Small Molecule Libraries/pharmacology , Acetylcholinesterase/metabolism , Cell Line , Cell Survival/drug effects , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , HeLa Cells , Humans , Models, Molecular , Molecular Structure , Small Molecule Libraries/chemistry , Soman/adverse effects , Structure-Activity Relationship
4.
ACS Chem Neurosci ; 9(5): 1074-1094, 2018 05 16.
Article in English | MEDLINE | ID: mdl-29345897

ABSTRACT

The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, ß-secretase, ß-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of ß-secretase (IC50  hBACE-1 = 41.60 µM), inhibition of amyloid ß aggregation (IC50 Aß = 3.09 µM), inhibition of tau aggregation (55% at 10 µM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50  hBuChE = 7.22 µM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer's agents.


Subject(s)
Alzheimer Disease/drug therapy , Butyrylcholinesterase/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Design , Alzheimer Disease/metabolism , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Humans , Molecular Docking Simulation/methods , Peptide Fragments/metabolism , Structure-Activity Relationship , tau Proteins/drug effects
5.
Molecules ; 22(8)2017 Jul 28.
Article in English | MEDLINE | ID: mdl-28788095

ABSTRACT

Tacrine (THA), the first clinically effective acetylcholinesterase (AChE) inhibitor and the first approved drug for the treatment of Alzheimer's disease (AD), was withdrawn from the market due to its side effects, particularly its hepatotoxicity. Nowadays, THA serves as a valuable scaffold for the design of novel agents potentially applicable for AD treatment. One such compound, namely 7-methoxytacrine (7-MEOTA), exhibits an intriguing profile, having suppressed hepatotoxicity and concomitantly retaining AChE inhibition properties. Another interesting class of AChE inhibitors represents Huprines, designed by merging two fragments of the known AChE inhibitors-THA and (-)-huperzine A. Several members of this compound family are more potent human AChE inhibitors than the parent compounds. The most promising are so-called huprines X and Y. Here, we report the design, synthesis, biological evaluation, and in silico studies of 2-methoxyhuprine that amalgamates structural features of 7-MEOTA and huprine Y in one molecule.


Subject(s)
Aminoquinolines/chemistry , Aminoquinolines/pharmacology , Drug Discovery , Acetylcholinesterase , Alzheimer Disease/drug therapy , Aminoquinolines/chemical synthesis , Binding Sites , Blood-Brain Barrier/metabolism , Butyrylcholinesterase , Catalytic Domain , Cell Line, Tumor , Cell Survival/drug effects , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Drug Design , Enzyme Activation/drug effects , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Hydrolysis , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Molecular Structure , Permeability , Protein Binding , Structure-Activity Relationship , Tacrine/analogs & derivatives , Tacrine/chemistry , Tacrine/pharmacology
6.
Molecules ; 22(7)2017 Jul 11.
Article in English | MEDLINE | ID: mdl-28696367

ABSTRACT

The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.


Subject(s)
Chemical Warfare Agents/poisoning , Cholinesterase Reactivators/therapeutic use , Neuroprotective Agents/therapeutic use , Organophosphate Poisoning/drug therapy , Organophosphates/toxicity , Oximes/therapeutic use , Pyridinium Compounds/therapeutic use , Acetylcholinesterase/metabolism , Animals , Atropine/therapeutic use , Brain/drug effects , Brain/enzymology , Humans , Male , Neurotoxicity Syndromes/drug therapy , Rats, Wistar , Trimedoxime/therapeutic use
7.
Molecules ; 22(6)2017 Jun 16.
Article in English | MEDLINE | ID: mdl-28621747

ABSTRACT

A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood-brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 ≥ 500 µM). Preliminary data also suggests a comparable hepatotoxic profile with 6-Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non-competitive enzyme inhibition. These findings were further corroborated by docking studies.


Subject(s)
Apigenin/chemistry , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Glucuronates/chemistry , Tacrine/analogs & derivatives , Acetylcholinesterase/metabolism , Alzheimer Disease/enzymology , Blood-Brain Barrier/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Drug Design , Enzyme Activation/drug effects , Humans , Molecular Docking Simulation , Structure-Activity Relationship , Tacrine/chemistry
8.
Eur J Med Chem ; 127: 250-262, 2017 Feb 15.
Article in English | MEDLINE | ID: mdl-28064079

ABSTRACT

Multi-target drug discovery is one of the most followed approaches in the active central nervous system (CNS) therapeutic area, especially in the search for new drugs against Alzheimer's disease (AD). This is because innovative multi-target-directed ligands (MTDLs) could more adequately address the complexity of this pathological condition. In a continuation of our efforts aimed at a new series of anti-AD MTDLs, we combined the structural features of the cholinesterase inhibitor drug tacrine with that of resveratrol, which is known for its purported antioxidant and anti-neuroinflammatory activities. The most interesting hybrid compounds (5, 8, 9 and 12) inhibited human acetylcholinesterase at micromolar concentrations and effectively modulated Aß self-aggregation in vitro. In addition, 12 showed intriguing anti-inflammatory and immuno-modulatory properties in neuronal and glial AD cell models. Importantly, the MTDL profile is accompanied by high-predicted blood-brain barrier permeability, and low cytotoxicity on primary neurons.


Subject(s)
Alzheimer Disease/drug therapy , Drug Design , Molecular Targeted Therapy , Stilbenes/chemistry , Tacrine/chemistry , Tacrine/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemistry , Animals , Antioxidants/chemistry , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Blood-Brain Barrier/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Humans , Ligands , Liver/drug effects , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Peptide Fragments/chemistry , Protein Aggregates/drug effects , Rats , Resveratrol , Tacrine/metabolism , Tacrine/therapeutic use
9.
Biochim Biophys Acta Mol Basis Dis ; 1863(2): 607-619, 2017 02.
Article in English | MEDLINE | ID: mdl-27865910

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and currently there is no efficient treatment. The classic drug-design strategy based on the "one-molecule-one-target" paradigm was found to be ineffective in the case of multifactorial diseases like AD. A novel multi-target-directed ligand strategy based on the assumption that a single compound consisting of two or more distinct pharmacophores is able to hit multiple targets has been proposed as promising. Herein, we investigated 7-methoxytacrine - memantine heterodimers developed with respect to the multi-target-directed ligand theory. The spectroscopic, microscopic and cell culture methods were used for systematic investigation of the interference of the heterodimers with ß-secretase (BACE1) activity, Aß peptide amyloid fibrillization (amyloid theory) and interaction with M1 subtype of muscarinic (mAChRs), nicotinic (nAChRs) acetylcholine receptors (cholinergic theory) and N-methyl-d-aspartate receptors (NMDA) (glutamatergic theory). The drug-like properties of selected compounds have been evaluated from the point of view of blood-brain barrier penetration and cell proliferation. We have confirmed the multipotent effect of novel series of compounds. They inhibited effectively Aß peptide amyloid fibrillization and affected the BACE1 activity. Moreover, they have AChE inhibitory potency but they could not potentiate cholinergic transmission via direct interaction with cholinergic receptors. All compounds were reported to act as an antagonist of both M1 muscarinic and muscle-type nicotinic receptors. We have found that 7-methoxytacrine - memantine heterodimers are able to hit multiple targets associated with Alzheimer's disease and thus, have a potential clinical impact for slowing or blocking the neurodegenerative process related to this disease.


Subject(s)
Alzheimer Disease/drug therapy , Amantadine/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Tacrine/analogs & derivatives , Alzheimer Disease/metabolism , Amantadine/analogs & derivatives , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Animals , CHO Cells , Cholinesterases/metabolism , Cricetulus , Dimerization , Enzyme Inhibitors/chemistry , HEK293 Cells , Humans , Molecular Targeted Therapy , Receptor, Muscarinic M1/antagonists & inhibitors , Receptor, Muscarinic M1/metabolism , Receptors, Cholinergic/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Tacrine/chemistry , Tacrine/pharmacology , Xenopus
10.
J Med Chem ; 59(21): 9967-9973, 2016 11 10.
Article in English | MEDLINE | ID: mdl-27736061

ABSTRACT

Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Antioxidants/pharmacology , Cholinesterase Inhibitors/pharmacology , Coumaric Acids/pharmacology , Melatonin/pharmacology , NF-E2-Related Factor 2/agonists , Antioxidants/chemical synthesis , Antioxidants/chemistry , Cell Death/drug effects , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterases/metabolism , Coumaric Acids/chemical synthesis , Coumaric Acids/chemistry , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Melatonin/chemical synthesis , Melatonin/chemistry , Molecular Structure , NF-E2-Related Factor 2/metabolism , Structure-Activity Relationship
11.
J Inorg Biochem ; 161: 52-62, 2016 08.
Article in English | MEDLINE | ID: mdl-27230386

ABSTRACT

Alzheimer's disease is a multifactorial disease that is characterized mainly by Amyloid-ß (A-ß) deposits, cholinergic deficit and extensive metal (copper, iron)-induced oxidative stress. In this work we present details of the synthesis, antioxidant and copper-chelating properties, DNA protection study, cholinergic activity and amyloid-antiaggregation properties of new multifunctional tacrine-7-hydroxycoumarin hybrids. The mode of interaction between copper(II) and hybrids and interestingly, the reduction of Cu(II) to Cu(I) species (for complexes Cu-5e-g) were confirmed by EPR measurements. EPR spin trapping on the model Fenton reaction, using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, demonstrated a significantly suppressed formation of hydroxyl radicals for the Cu-5e complex in comparison with free copper(II). This suggests that compound 5e upon coordination to free copper ion prevents the Cu(II)-catalyzed decomposition of hydrogen peroxide, which in turn may alleviate oxidative stress-induced damage. Protective activity of hybrids 5c and 5e against DNA damage in a Fenton system (copper catalyzed) was found to be in excellent agreement with the EPR spin trapping study. Compound 5g was the most effective in the inhibition of acetylcholinesterase (hAChE, IC50=38nM) and compound 5b was the most potent inhibitor of butyrylcholinesterase (hBuChE, IC50=63nM). Compound 5c was the strongest inhibitor of A-ß1-40 aggregation, although a significant inhibition (>50%) was detected for compounds 5b, 5d, 5e and 5g. Collectively, these results suggest that the design and investigation of multifunctional agents containing along with the acetylcholinesterase inhibitory segment also an antioxidant moiety capable of alleviating metal (copper)-induced oxidative stress, may be of importance in the treatment of Alzheimer's disease.


Subject(s)
Acetylcholinesterase/chemistry , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/chemistry , Cholinesterase Inhibitors , Copper/chemistry , Coumarins , Oxidative Stress , Peptide Fragments/chemistry , Tacrine , Alzheimer Disease/metabolism , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Coumarins/chemical synthesis , Coumarins/chemistry , GPI-Linked Proteins/chemistry , Humans , Tacrine/chemical synthesis , Tacrine/chemistry
12.
ChemMedChem ; 11(12): 1264-9, 2016 06 20.
Article in English | MEDLINE | ID: mdl-26427608

ABSTRACT

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 µm), butyrylcholinesterase (BChE IC50 : 2.4 µm) and MAO A (IC50 : 0.49 µm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 µm). Although its cytotoxic (IC50 : 5.5±0.4 µm) and hepatotoxic (IC50 : 1.22±0.11 µm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77 µm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Drug Design , Indoles/chemical synthesis , Monoamine Oxidase Inhibitors/therapeutic use , Quinolines/chemical synthesis , Tacrine/chemistry , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Blood-Brain Barrier/metabolism , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/toxicity , Hep G2 Cells , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/therapeutic use , Indoles/toxicity , Inhibitory Concentration 50 , Ligands , Monoamine Oxidase/chemistry , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/toxicity , Quinolines/chemistry , Quinolines/metabolism , Quinolines/therapeutic use , Quinolines/toxicity , Structure-Activity Relationship , Tacrine/metabolism , Tacrine/therapeutic use , Tacrine/toxicity
13.
Molecules ; 20(12): 22084-101, 2015 Dec 10.
Article in English | MEDLINE | ID: mdl-26690394

ABSTRACT

Alzheimer's disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient's death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds' behavior was confirmed in the subsequent molecular modeling studies.


Subject(s)
Acetylcholinesterase/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Aniline Compounds/chemistry , Central Nervous System Agents/chemistry , Cholinesterase Inhibitors/chemistry , Tacrine/analogs & derivatives , Amyloid beta-Peptides/chemistry , Aniline Compounds/chemical synthesis , Binding Sites , Central Nervous System Agents/chemical synthesis , Cholinesterase Inhibitors/chemical synthesis , Humans , Kinetics , Molecular Docking Simulation , Recombinant Proteins/chemistry , Structure-Activity Relationship
14.
J Med Chem ; 58(22): 8985-9003, 2015 Nov 25.
Article in English | MEDLINE | ID: mdl-26503905

ABSTRACT

Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.


Subject(s)
Antioxidants/chemical synthesis , Antioxidants/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Chromans/chemistry , Chromans/pharmacology , Tacrine/chemistry , Tacrine/pharmacology , Acetylcholinesterase/chemistry , Animals , Antioxidants/toxicity , Blood-Brain Barrier , Catalysis , Cholinesterase Inhibitors/toxicity , Chromans/toxicity , Drug Design , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/pharmacology , Hepatocytes/drug effects , Humans , Injections, Intramuscular , Kinetics , Ligands , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Rats , Rats, Wistar , Tacrine/toxicity
15.
Toxicol Mech Methods ; 25(3): 229-33, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25894563

ABSTRACT

The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 µg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.


Subject(s)
Antidotes/therapeutic use , Cholinesterase Inhibitors/toxicity , Cholinesterase Reactivators/therapeutic use , Neurotoxicity Syndromes/drug therapy , Oximes/therapeutic use , Pyridinium Compounds/therapeutic use , Sarin/toxicity , Acetylcholinesterase/blood , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Animals , Animals, Outbred Strains , Atropine/therapeutic use , Brain/drug effects , Brain/enzymology , Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/chemistry , Diaphragm/drug effects , Diaphragm/enzymology , Dose-Response Relationship, Drug , Drug Therapy, Combination , Male , Mice , Muscarinic Antagonists/therapeutic use , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/enzymology , Neurotoxicity Syndromes/blood , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/metabolism , Obidoxime Chloride/therapeutic use , Rats, Wistar , Sarin/administration & dosage , Sarin/antagonists & inhibitors
16.
Basic Clin Pharmacol Toxicol ; 116(4): 367-71, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25225130

ABSTRACT

The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun-poisoned rats and mice. The oxime-induced reactivation of tabun-inhibited acetylcholinesterase was measured in diaphragm and brain of tabun-poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun-inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun-inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5-fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.


Subject(s)
Antidotes/therapeutic use , Chemical Warfare Agents/toxicity , Cholinesterase Inhibitors/toxicity , Cholinesterase Reactivators/therapeutic use , Organophosphates/toxicity , Oximes/therapeutic use , Pyridinium Compounds/therapeutic use , Trimedoxime/therapeutic use , Animals , Atropine/pharmacology , Injections, Intramuscular , Lethal Dose 50 , Male , Mice , Parasympatholytics/pharmacology , Rats , Rats, Wistar
17.
Gen Physiol Biophys ; 34(2): 189-200, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25504063

ABSTRACT

Organophosphorus nerve agents inhibit acetylcholinesterase (AChE) which causes the breakdown of the transmitter acetylcholine (ACh) in the synaptic cleft. Overstimulation of cholinergic receptors (muscarinic and nicotinic) by excessive amounts of ACh causes several health problems and may even cause death. Reversible AChE inhibitors play an important role in prophylaxis against nerve agents. The presented study investigated whether 7-methoxytacrine (7-MEOTA) and 7-MEOTA-donepezil derivatives can act as central and peripheral reversible AChE inhibitors and simultaneously antagonize muscarinic and nicotinic receptors. The possible mechanism of action was studied on cell cultures (patch clamp technique, calcium mobilization assay) and on isolated smooth muscle tissue (contraction study). Furthermore, the kinetics of the compounds were also examined. CNS availability was predicted by determining the passive blood-brain barrier penetration estimated via a modified PAMPA assay. In conclusion, this study provides promising evidence that the new synthesized 7-MEOTA-donepezil derivatives have the desired anticholinergic effect; they can inhibit AChE, and nicotinic and muscarinic receptors in the micromolar range. Furthermore, they seem to penetrate readily into the CNS. However, their real potency and benefit must be verified by in vivo experiments.


Subject(s)
Cholinergic Antagonists/administration & dosage , Indans/administration & dosage , Muscarinic Antagonists/administration & dosage , Muscle Fibers, Skeletal/metabolism , Nicotinic Antagonists/administration & dosage , Piperidines/administration & dosage , Tacrine/analogs & derivatives , Animals , Cells, Cultured , Donepezil , Dose-Response Relationship, Drug , Male , Muscle Fibers, Skeletal/drug effects , Rats , Rats, Wistar , Tacrine/administration & dosage
18.
Eur J Med Chem ; 82: 426-38, 2014 Jul 23.
Article in English | MEDLINE | ID: mdl-24929293

ABSTRACT

A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment.


Subject(s)
Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Indans/pharmacology , Piperidines/pharmacology , Quantitative Structure-Activity Relationship , Tacrine/analogs & derivatives , Animals , Butyrylcholinesterase/blood , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Donepezil , Dose-Response Relationship, Drug , Electrophorus , Horses , Humans , Indans/chemistry , Models, Molecular , Molecular Structure , Piperidines/chemistry , Recombinant Proteins/metabolism , Tacrine/chemistry , Tacrine/pharmacology
19.
Basic Clin Pharmacol Toxicol ; 115(6): 571-6, 2014 Dec.
Article in English | MEDLINE | ID: mdl-24842281

ABSTRACT

The ability of four newly developed reversible inhibitors of acetylcholinesterase (PC-37, PC-48, JaKo 39, JaKo 40) and currently available carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated and compared. No reversible inhibitor of acetylcholinesterase studied was able to decrease the LD50 value of soman in mice. Thus, the pharmacological pre-treatment with pyridostigmine or newly synthesized inhibitors of acetylcholinesterase was not able to significantly protect mice against soman-induced lethal acute toxicity. In addition, neither pyridostigmine nor new reversible inhibitors of acetylcholinesterase was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. These findings demonstrate that pharmacological pre-treatment of soman-poisoned mice with tested reversible inhibitors of acetylcholinesterase is not promising.


Subject(s)
Antidotes/therapeutic use , Cholinesterase Inhibitors/therapeutic use , Piperazines/therapeutic use , Pyridostigmine Bromide/therapeutic use , Soman/poisoning , Tacrine/analogs & derivatives , Animals , Lethal Dose 50 , Male , Mice , Soman/antagonists & inhibitors , Tacrine/therapeutic use
20.
Expert Opin Drug Saf ; 13(6): 759-74, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24845946

ABSTRACT

INTRODUCTION: Alzheimer's disease (AD) is a world-wide health problem with implications for an increasing number of people and countries. Populations suffering from AD financially strain the healthcare budgets of rich and poor countries alike. Moreover, no effective treatment is available and current drugs merely slow the progression of cognitive function deterioration and overall health status toward an inevitable end point. An increasing number of novel approaches have been tested in numerous clinical trials, but none of them has proved safe and effective for treating AD. AREAS COVERED: This review summarizes all currently available compounds (donepezil, rivastigmine, galantamine, memantine) for the management of AD, concentrating on clinical aspects such as the mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. This review also considers the mechanisms and side effects to provide perspective on current treatment options. EXPERT OPINION: Novel approaches in the treatment of AD are being intensively tested, but so far without any major success. Patients diagnosed with AD still mostly benefit from four compounds to significantly improve cognition functions and overall health and help manage other symptoms or even prolong the symptom-free period.


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Memantine/therapeutic use , Alzheimer Disease/epidemiology , Alzheimer Disease/physiopathology , Animals , Cholinesterase Inhibitors/adverse effects , Cholinesterase Inhibitors/pharmacology , Clinical Trials as Topic , Disease Progression , Drug Design , Excitatory Amino Acid Antagonists/adverse effects , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acid Antagonists/therapeutic use , Humans , Memantine/adverse effects , Memantine/pharmacology , Treatment Outcome
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