Dohnal V

References (27)

Title : Monooxime Bispyridinium Reactivators Bearing Xylene Linker Synthesis and In Vitro Evaluation on Model of Organophosphate-Inhibited Acetylcholinesterase - Musilek_2016_Med.Chem_12_362
Author(s) : Musilek K , Hambalek J , Holas O , Dohnal V , Kuca K
Ref : Med Chem , 12 :362 , 2016
Abstract : Nine novel mono-oxime reactivators bearing xylene linker were synthesized in an effort to improve previously prepared xylene bisoximes and monocarbamoyl-monooximes. The novel compounds were tested in vitro on the model of tabun-, paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Their reactivation ability was compared to pralidoxime, asoxime, obidoxime and two previously prepared xylene linked bisoximes (K107, K108). All compounds showed minimal reactivation of tabun-inhibited AChE at selected concentration scale. This finding was explained by molecular modelling study. Bisoximes obidoxime and K108 resulted as the best reactivators for paraoxon-, methylparaoxon- and DFP-inhibited AChE. The loss of nonoxime moiety lead to the loss of reactivation ability within the novel compounds. Though the novel reactivators did not exceed previously known compounds, they confirmed former SAR findings for xylene-linked AChE reactivators.
ESTHER : Musilek_2016_Med.Chem_12_362
PubMedSearch : Musilek_2016_Med.Chem_12_362
PubMedID: 26427931

Title : Development and validation of a FIA\/UV-vis method for pK determination of oxime based acetylcholinesterase reactivators - Musil_2015_J.Pharm.Biomed.Anal_117_240
Author(s) : Musil K , Florianova V , Bucek P , Dohnal V , Kuca K , Musilek K
Ref : J Pharm Biomed Anal , 117 :240 , 2015
Abstract : Acetylcholinesterase reactivators (oximes) are compounds used for antidotal treatment in case of organophosphorus poisoning. The dissociation constants (pKa1) of ten standard or promising acetylcholinesterase reactivators were determined by ultraviolet absorption spectrometry. Two methods of spectra measurement (UV-vis spectrometry, FIA/UV-vis) were applied and compared. The soft and hard models for calculation of pKa1 values were performed. The pKa1 values were recommended in the range 7.00-8.35, where at least 10% of oximate anion is available for organophosphate reactivation. All tested oximes were found to have pKa1 in this range. The FIA/UV-vis method provided rapid sample throughput, low sample consumption, high sensitivity and precision compared to standard UV-vis method. The hard calculation model was proposed as more accurate for pKa1 calculation.
ESTHER : Musil_2015_J.Pharm.Biomed.Anal_117_240
PubMedSearch : Musil_2015_J.Pharm.Biomed.Anal_117_240
PubMedID: 26386953

Title : Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update - Wu_2014_Arch.Toxicol_88_1309
Author(s) : Wu QH , Wang X , Yang W , Nussler AK , Xiong LY , Kuca K , Dohnal V , Zhang XJ , Yuan ZH
Ref : Archives of Toxicology , 88 :1309 , 2014
Abstract : Trichothecenes are a large family of structurally related toxins mainly produced by Fusarium genus. Among the trichothecenes, T-2 toxin and deoxynivalenol (DON) cause the most concern due to their wide distribution and highly toxic nature. Trichothecenes are known for their inhibitory effect on eukaryotic protein synthesis, and oxidative stress is one of their most important underlying toxic mechanisms. They are able to generate free radicals, including reactive oxygen species, which induce lipid peroxidation leading to changes in membrane integrity, cellular redox signaling, and in the antioxidant status of the cells. The mitogen-activated protein kinases signaling pathway is induced by oxidative stress, which also induces caspase-mediated cellular apoptosis pathways. Several new metabolites and novel metabolic pathways of T-2 toxin have been discovered very recently. In human cell lines, HT-2 and neosolaniol (NEO) are the major metabolites of T-2 toxin. Hydroxylation on C-7 and C-9 are two novel metabolic pathways of T-2 toxin in rats. The metabolizing enzymes CYP3A22, CYP3A29, and CYP3A46 in pigs, as well as the enzymes CYP1A5 and CYP3A37 in chickens, are able to catalyze T-2 toxin and HT-2 toxin to form the C-3'-OH metabolites. Similarly to carboxylesterase, CYP3A29 possesses the hydrolytic ability in pigs to convert T-2 toxin to NEO. T-2 toxin is able to down- or upregulate cytochrome P-450 enzymes in different species. The metabolism of DON in humans is region-dependent. Free DON and DON-glucuronide are considered to be the biomarkers for humans. The masked mycotoxin DON-3-beta-D-glucoside can be hydrolyzed to free DON in the body. This review will provide useful information on the progress of oxidative stress as well as on the metabolism and the metabolizing enzymes of T-2 toxin and DON. Moreover, the literature will throw light on the blind spots of metabolism and toxicological studies in trichothecenes that have to be explored in the future.
ESTHER : Wu_2014_Arch.Toxicol_88_1309
PubMedSearch : Wu_2014_Arch.Toxicol_88_1309
PubMedID: 24894432

Title : Preparation, in vitro screening and molecular modelling of monoquaternary compounds related to the selective acetylcholinesterase inhibitor BW284c51 - Benek_2014_Med.Chem_11_21
Author(s) : Benek O , Musilek K , Horova A , Dohnal V , Dolezal R , Kuca K
Ref : Med Chem , 11 :21 , 2014
Abstract : This paper describes preparation and in vitro evaluation of 19 compounds related to the selective experimental cholinesterase inhibitor BW284c51. The novel compounds were prepared as fragments of parent molecule BW284c51 and evaluated on the model of human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase. The IC(5)(0) values of the prepared compounds were compared to the parent molecule BW284c51. None of the compounds was superior to the parent drug, but two BW284c51 fragments showed promising hAChE inhibition in microM scale and improved selectivity. These two fragments were further subjected to the molecular modelling study and their enzyme interactions were rationalized. The structure-activity relationship of the prepared series was stated.
ESTHER : Benek_2014_Med.Chem_11_21
PubMedSearch : Benek_2014_Med.Chem_11_21
PubMedID: 24773345

Title : selective monitoring of enzymatic activity of acetylcholinesterase by flow injection analysis with mass spectrometric detection - Dohnal_2013_Mil.Med.Sci.Lett_82_120
Author(s) : Dohnal V , Dohnalova L , Jun D , Kuca K
Ref : Military Medical Science Letters , 82 :120 , 2013
Abstract : Flow injection analysis (FIA) is an analytical method where the reaction mixture is injected into flow of liquid. The reaction product is monitored by a suitable detector such as ultraviolet/visible (UV/VIS) spectrophotometric or electrochemical detector. Mass spectrometric detectors (MS) are coming to be a standard equipment of analytical laboratories in the present time. This work is focused on application of FIA-MS instrumentation for monitoring of Ellman's reaction where both reactants (acetylthiocholine and 5,5'-dithiobis-2-nitrobenzoic acid, DTNB) and the reaction product (5-mercapto-2-nitrobenzoic acid) are monitored. This reaction is usually used for monitoring of acetylcholinesterase and butyrylcholinesterase. Due to its simplicity, the developed method is generally applicable for monitoring of enzymatic reactions of cholinesterases. The main advantage of this method is high selectivity and reduction of influence of compounds, which are reacting with DTNB, resulting in a color product of Ellman's reaction.
ESTHER : Dohnal_2013_Mil.Med.Sci.Lett_82_120
PubMedSearch : Dohnal_2013_Mil.Med.Sci.Lett_82_120
PubMedID:

Title : Preparation, in vitro screening and molecular modelling of symmetrical 4-tert-butylpyridinium cholinesterase inhibitors--analogues of SAD-128 - Musilek_2011_Bioorg.Med.Chem.Lett_21_150
Author(s) : Musilek K , Roder J , Komloova M , Holas O , Hrabinova M , Pohanka M , Dohnal V , Opletalova V , Kuca K , Jung YS
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :150 , 2011
Abstract : Carbamate inhibitors (e.g., pyridostimine bromide) are used as a pre-exposure treatment for the prevention of organophosphorus poisoning. They work by blocking acetylcholinesterase's (AChE) native function and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for many undesirable side-effects related to the carbamylation of AChE. In this Letter, 19 analogues of SAD-128 were prepared and evaluated as cholinesterase inhibitors. The screening results showed promising inhibitory ability of four compounds better to used standards (pralidoxime, obidoxime, BW284c51, ethopropazine, SAD-128). Four most promising compounds were selected for further molecular docking studies. The SAR was stated from obtained data. The former receptor studies were reported and discussed. The further in vivo studies were recommended in the view of OP pre-exposure treatment.
ESTHER : Musilek_2011_Bioorg.Med.Chem.Lett_21_150
PubMedSearch : Musilek_2011_Bioorg.Med.Chem.Lett_21_150
PubMedID: 21144749

Title : Preparation, in vitro screening and molecular modelling of symmetrical bis-quinolinium cholinesterase inhibitors--implications for early myasthenia gravis treatment - Komloova_2011_Bioorg.Med.Chem.Lett_21_2505
Author(s) : Komloova M , Musilek K , Horova A , Holas O , Dohnal V , Gunn-Moore F , Kuca K
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :2505 , 2011
Abstract : This paper describes the preparation and in vitro evaluation of 18 newly prepared bis-quinolinium inhibitors on human recombinant acetylcholinesterase (AChE) and human plasmatic butyrylcholinesterase (BChE). Their inhibitory (IC(50)) and was compared to the chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. One novel compound was found to be a promising inhibitor of hAChE (in nM range) and was better than edrophonium chloride or BW284c51, but was worse than ambenonium chloride. This compound also showed selectivity towards hAChE and it was confirmed as a non-competitive inhibitor of hAChE by kinetic analysis. A molecular modelling study further confirmed its binding to the peripheral active site of hAChE via apparent pi-pi or pi-cationic interactions.
ESTHER : Komloova_2011_Bioorg.Med.Chem.Lett_21_2505
PubMedSearch : Komloova_2011_Bioorg.Med.Chem.Lett_21_2505
PubMedID: 21397501

Title : Mono-oxime bisquaternary acetylcholinesterase reactivators with prop-1,3-diyl linkage-Preparation, in vitro screening and molecular docking - Musilek_2011_Bioorg.Med.Chem_19_754
Author(s) : Musilek K , Komloova M , Holas O , Horova A , Pohanka M , Gunn-Moore F , Dohnal V , Dolezal M , Kuca K
Ref : Bioorganic & Medicinal Chemistry , 19 :754 , 2011
Abstract : The treatment of organophosphorus (OP) poisoning consists of the administration of a parasympatholytic agent (e.g., atropine), an anticonvulsant (e.g., diazepam) and an acetylcholinesterase (AChE) reactivator (e.g., obidoxime). The AChE reactivator is the causal treatment of OP exposure, because it cleaves the OP moiety covalently bound to the AChE active site. In this paper, fourteen novel AChE reactivators are described. Their design originated from a former promising compound K027. These compounds were synthesized, evaluated in vitro on human AChE (hAChE) inhibited by tabun, paraoxon, methylparaoxon and DFP and then compared to commercial hAChE reactivators (pralidoxime, HI-6, trimedoxime, obidoxime, methoxime) or previously prepared compounds (K027, K203). Three of these novel compounds showed a promising ability to reactivate hAChE comparable or better than the used standards. Consequently, a molecular docking study was performed for three of these promising novel compounds. The docking results confirmed the apparent influence of pi-pi or cation-pi interactions and hydrogen bonding for reactivator binding within the hAChE active site cleft. The SAR features concerning the non-oxime part of the reactivator molecule are also discussed.
ESTHER : Musilek_2011_Bioorg.Med.Chem_19_754
PubMedSearch : Musilek_2011_Bioorg.Med.Chem_19_754
PubMedID: 21215642

Title : Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment - Musilek_2011_Eur.J.Med.Chem_46_811
Author(s) : Musilek K , Komloova M , Holas O , Hrabinova M , Pohanka M , Dohnal V , Nachon F , Dolezal M , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 46 :811 , 2011
Abstract : Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer's disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood-brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non-competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent pi-pi or pi-cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed.
ESTHER : Musilek_2011_Eur.J.Med.Chem_46_811
PubMedSearch : Musilek_2011_Eur.J.Med.Chem_46_811
PubMedID: 21236521

Title : The preparation, in vitro screening and molecular docking of symmetrical bisquaternary cholinesterase inhibitors containing a but-(2E)-en-1,4-diyl connecting linkage - Musilek_2011_J.Enzyme.Inhib.Med.Chem_26_245
Author(s) : Musilek K , Pavlikova R , Marek J , Komloova M , Holas O , Hrabinova M , Pohanka M , Dohnal V , Dolezal M , Gunn-Moore F , Kuca K
Ref : J Enzyme Inhib Med Chem , 26 :245 , 2011
Abstract : Carbamate inhibitors (e.g. pyridostigmine bromide) are used as a pre-treatment for the prevention of organophosphorus poisoning. They work by blocking the native function of acetylcholinesterases (AChE) and thus protect AChE against irreversible inhibition by organophosphorus compounds. However, carbamate inhibitors are known for their many undesirable side effects related to the carbamylation of AChE. In this paper, we describe 17 novel bisquaternary compounds and have analysed their effect on AChE inhibition. The newly prepared compounds were evaluated in vitro using both human erythrocyte AChE and human plasmatic butyrylcholinesterase. Their inhibitory ability was expressed as the half maximal inhibitory concentration (IC(5)(0)) and then compared to the standard carbamate drugs and two AChE reactivators. One of these novel compounds showed promising AChE inhibition in vitro (nM range) and was better than the currently used standards. Additionally, a kinetic assay confirmed the non-competitive inhibition of hAChE by this novel compound. Consequently, the docking results confirmed the apparent pi-pi or pi-cationic interactions with the key amino acid residues of hAChE and the binding of the chosen compound at the enzyme catalytic site.
ESTHER : Musilek_2011_J.Enzyme.Inhib.Med.Chem_26_245
PubMedSearch : Musilek_2011_J.Enzyme.Inhib.Med.Chem_26_245
PubMedID: 21406034

Title : Monooxime-monocarbamoyl Bispyridinium Xylene-Linked Reactivators of Acetylcholinesterase-Synthesis, In vitro and Toxicity Evaluation, and Docking Studies - Musilek_2010_ChemMedChem_5_247
Author(s) : Musilek K , Holas O , Misik J , Pohanka M , Novotny L , Dohnal V , Opletalova V , Kuca K
Ref : ChemMedChem , 5 :247 , 2010
Abstract : Acetylcholinesterase (AChE) reactivators are crucial antidotes to organophosphate intoxication. A new series of 26 monooxime-monocarbamoyl xylene-linked bispyridinium compounds was prepared and tested in vitro, along with known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime, K107, K108 and K203), on a model of tabun- and paraoxon-, methylparaoxon- and DFP-inhibited human erythrocyte AChE. Although their ability to reactivate tabun-inhibited AChE did not exceed that of the previously known compounds, some newly prepared compounds showed promising reactivation of pesticide-inhibited AChE. The acute toxicity of the novel compounds was also determined. Docking studies using tabun-inhibited AChE were performed for three compounds of interest. The structure-activity relationship (SAR) study confirmed the apparent influence of the xylene linkage and carbamoyl moiety on the reactivation ability and toxicity of the agents.
ESTHER : Musilek_2010_ChemMedChem_5_247
PubMedSearch : Musilek_2010_ChemMedChem_5_247
PubMedID: 20058292

Title : Preparation and in vitro screening of symmetrical bispyridinium cholinesterase inhibitors bearing different connecting linkage-initial study for Myasthenia gravis implications - Musilek_2010_Bioorg.Med.Chem.Lett_20_1763
Author(s) : Musilek K , Komloova M , Zavadova V , Holas O , Hrabinova M , Pohanka M , Dohnal V , Nachon F , Dolezal M , Kuca K , Jung YS
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :1763 , 2010
Abstract : Reversible inhibitors (e.g., pyridostigmine bromide, neostigmine bromide) of carbamate origin are used in the early treatment of Myasthenia gravis (MG) to block acetylcholinesterase (AChE) native function and conserve efficient amount of acetylcholine for decreasing number of nicotinic receptors. Carbamate inhibitors are known for many undesirable side effects related to the reversible inhibition of AChE. In contrast, this paper describes 20 newly prepared bispyridinium inhibitors of potential concern for MG. Although some compounds from this series have been known before, they were not assayed for cholinesterase inhibition yet. The newly prepared compounds were evaluated in vitro on human erythrocyte AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC(50) and compared to standard carbamate drugs. Three compounds presented promising inhibition (in muM range) of both enzymes in vitro similar to the used standards. The novel inhibitors did not present selectivity between AChE and BChE. Two newly prepared compounds were chosen for docking studies and confirmed apparent pi-pi or pi-cationic interactions aside enzyme's catalytic sites. The kinetics assay confirmed non-competitive inhibition of AChE by two best newly prepared compounds.
ESTHER : Musilek_2010_Bioorg.Med.Chem.Lett_20_1763
PubMedSearch : Musilek_2010_Bioorg.Med.Chem.Lett_20_1763
PubMedID: 20138518

Title : Synthesis and in vitro evaluation of N-(Bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a cholinesterase inhibitor with regard to Alzheimer's disease treatment - Korabecny_2010_Molecules_15_8804
Author(s) : Korabecny J , Musilek K , Holas O , Nepovimova E , Jun D , Zemek F , Opletalova V , Patocka J , Dohnal V , Nachon F , Hroudova J , Fisar Z , Kuca K
Ref : Molecules , 15 :8804 , 2010
Abstract : A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.
ESTHER : Korabecny_2010_Molecules_15_8804
PubMedSearch : Korabecny_2010_Molecules_15_8804
PubMedID: 21127466

Title : Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease - Korabecny_2010_Bioorg.Med.Chem.Lett_20_6093
Author(s) : Korabecny J , Musilek K , Holas O , Binder J , Zemek F , Marek J , Pohanka M , Opletalova V , Dohnal V , Kuca K
Ref : Bioorganic & Medicinal Chemistry Lett , 20 :6093 , 2010
Abstract : All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9-amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7-methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C(6)-C(7)N-alkyl chains for cholinesterase inhibition.
ESTHER : Korabecny_2010_Bioorg.Med.Chem.Lett_20_6093
PubMedSearch : Korabecny_2010_Bioorg.Med.Chem.Lett_20_6093
PubMedID: 20817518

Title : Monoquaternary pyridinium salts with modified side chain-synthesis and evaluation on model of tabun- and paraoxon-inhibited acetylcholinesterase - Musilek_2008_Bioorg.Med.Chem_16_8218
Author(s) : Musilek K , Kucera J , Jun D , Dohnal V , Opletalova V , Kuca K
Ref : Bioorganic & Medicinal Chemistry , 16 :8218 , 2008
Abstract : Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Eighteen monoquaternary reactivators of acetylcholinesterase with modified side chain were developed in an effort to extend the properties of pralidoxime. The known reactivators (pralidoxime, HI-6, obidoxime, trimedoxime, methoxime) and the prepared compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monoquaternary reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation better or comparable with pralidoxime for paraoxon poisoning. However, extensive differences were found by a SAR study for various side chains on the non-oxime part of the reactivator molecule.
ESTHER : Musilek_2008_Bioorg.Med.Chem_16_8218
PubMedSearch : Musilek_2008_Bioorg.Med.Chem_16_8218
PubMedID: 18676153

Title : Synthesis of monooxime-monocarbamoyl bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against tabun- and paraoxon-inhibited acetylcholinesterase - Musilek_2008_J.Enzyme.Inhib.Med.Chem_23_70
Author(s) : Musilek K , Holas O , Kuca K , Jun D , Dohnal V , Opletalova V , Dolezal M
Ref : J Enzyme Inhib Med Chem , 23 :70 , 2008
Abstract : Six AChE monooxime-monocarbamoyl reactivators with an (E)-but-2-ene linker were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by the nerve agent tabun and insecticide paraoxon was tested in vitro. The reactivation efficacies of pralidoxime, HI-6, obidoxime, K048, K075 and the newly prepared reactivators were compared. According to the results obtained, one reactivator seems to be promising against tabun-inhibited AChE and two reactivators against paraoxon-inhibited AChE. The best results were obtained for bisquaternary substances with at least one oxime group in position four.
ESTHER : Musilek_2008_J.Enzyme.Inhib.Med.Chem_23_70
PubMedSearch : Musilek_2008_J.Enzyme.Inhib.Med.Chem_23_70
PubMedID: 18341256

Title : Synthesis of a novel series of non-symmetrical bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase - Musilek_2007_J.Enzyme.Inhib.Med.Chem_22_425
Author(s) : Musilek K , Holas O , Kuca K , Jun D , Dohnal V , Dolezal M
Ref : J Enzyme Inhib Med Chem , 22 :425 , 2007
Abstract : Nine potential non-symmetrical xylene-bridged AChE reactivators were synthesized using modifications of currently known synthetic pathways. Their potency to reactivate AChE inhibited by the nerve agent tabun and the insecticide paraoxon together with nine symmetrical xylene-bridged compounds, was tested in vitro. Seven compounds were promising against paraoxon-inhibited AChE. Two compounds were found to be more potent against tabun-inhibited AChE than obidoxime at a concentration applicable in vivo.
ESTHER : Musilek_2007_J.Enzyme.Inhib.Med.Chem_22_425
PubMedSearch : Musilek_2007_J.Enzyme.Inhib.Med.Chem_22_425
PubMedID: 17847708

Title : Two step synthesis of a non-symmetric acetylcholinesterase reactivator - Musilek_2007_Molecules_12_1755
Author(s) : Musilek K , Kuca K , Dohnal V , Jun D , Marek J , Koleckar V
Ref : Molecules , 12 :1755 , 2007
Abstract : The newly developed and very promising acetylcholinesterase reactivator (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-e ne dibromide was prepared using two different pathways via a two-step synthesis involving the appropriate (E)-1-(4-bromobut-2-enyl)-2- or 4-hydroxyiminomethyl-pyridinium bromides. Afterwards, purities and yields of the desired product prepared by both routes were compared. Finally, its potency to reactivate several nerve agent-inhibited acetylcholinesterases was tested.
ESTHER : Musilek_2007_Molecules_12_1755
PubMedSearch : Musilek_2007_Molecules_12_1755
PubMedID: 17960085

Title : Monooxime reactivators of acetylcholinesterase with (E)-but-2-ene linker: preparation and reactivation of tabun- and paraoxon-inhibited acetylcholinesterase - Musilek_2007_Bioorg.Med.Chem_15_6733
Author(s) : Musilek K , Holas O , Jun D , Dohnal V , Gunn-Moore F , Opletalova V , Dolezal M , Kuca K
Ref : Bioorganic & Medicinal Chemistry , 15 :6733 , 2007
Abstract : Acetylcholinesterase reactivators are crucial antidotes for the treatment of organophosphate intoxication. Fifteen new monooxime reactivators of acetylcholinesterase with a (E)-but-2-ene linker were developed in an effort to extend the properties of K-oxime (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). The known reactivators (pralidoxime, HI-6, obidoxime, K075, K203) and the new compounds were tested in vitro on a model of tabun- and paraoxon-inhibited AChE. Monooxime reactivators were not able to exceed the best known compounds for tabun poisoning, but some of them did show reactivation comparable with known compounds for paraoxon poisoning. However, extensive differences were found by a SAR study for various substitutions on the non-oxime part of the reactivator molecule.
ESTHER : Musilek_2007_Bioorg.Med.Chem_15_6733
PubMedSearch : Musilek_2007_Bioorg.Med.Chem_15_6733
PubMedID: 17764957

Title : Novel series of bispyridinium compounds bearing a (Z)-but-2-ene linker--synthesis and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase - Musilek_2007_Bioorg.Med.Chem.Lett_17_3172
Author(s) : Musilek K , Holas O , Kuca K , Jun D , Dohnal V , Opletalova V , Dolezal M
Ref : Bioorganic & Medicinal Chemistry Lett , 17 :3172 , 2007
Abstract : Six novel AChE reactivators with a (Z)-but-2-ene linker were synthesized using the known synthetic pathways. Their ability to reactivate AChE, which had been previously inhibited by nerve agent tabun or pesticide paraoxon, was tested in vitro and compared to pralidoxime, HI-6, obidoxime, and K075. The novel synthesized compounds were found to be ineffective against GA-inhibited AChE but the ability of (Z)-1,4-bis(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide to reactivate paraoxon-inhibited AChE was comparable with that of oxime K075. Notably, the oxime group in position four substantially increased the ability of the novel compounds to reactivate paraoxon-inhibited AChE.
ESTHER : Musilek_2007_Bioorg.Med.Chem.Lett_17_3172
PubMedSearch : Musilek_2007_Bioorg.Med.Chem.Lett_17_3172
PubMedID: 17383875

Title : [Synthesis of reactivators of phosphorylated acetylcholinesterase of bis-pyridiniumdialdoxime type with a 3-oxapentane connecting chain and their testing in vitro on a model of the enzyme inhibited by chlorpyrifos and methylchlorpyrifos] - Musilek_2006_Ceska.Slov.Farm_55_115
Author(s) : Musilek K , Kuca K , Jun D , Dohnal V , Kim TH , Jung YS , Dolezal M
Ref : Ceska a Slovenska Farmacie , 55 :115 , 2006
Abstract : Insecticides (e.g., parathion, chlorpyrifos, methylchlorpyrifos) and nerve agents (e.g.. soman, sarin, tabun, VX) belong to the group of organophosphates. They are able to irreversibly inhibit the enzyme acetylcholinesterase (AChE). Three new reactivators with a 3-oxapentane connecting chain were prepared. The ability of the new compounds to reactivate AChE inhibited by pesticides was tested in vitro and compared to known oxime 10(-3) M which is unfortunately not applicable to in vivo experiments. All tested compounds are practically ineffective for methylchlorpyrifos-inhibited AChE at the physiological concentration (10(-5) M). On the other hand, the known reactivators surpass new substances in the case of chlorpyrifos-inhibited AChE at both concentrations.
ESTHER : Musilek_2006_Ceska.Slov.Farm_55_115
PubMedSearch : Musilek_2006_Ceska.Slov.Farm_55_115
PubMedID: 16838488

Title : Synthesis of asymmetrical bispyridinium compounds bearing cyano-moiety and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase - Musilek_2006_Bioorg.Med.Chem.Lett_16_5673
Author(s) : Musilek K , Holas O , Kuca K , Jun D , Dohnal V , Dolezal M
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :5673 , 2006
Abstract : Three asymmetrical AChE reactivators with cyano-moiety and propane linker were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by nerve agent tabun and insecticide paraoxon was tested in vitro and compared to pralidoxime, HI-6, obidoxime, K027, and K048. According to the results, three compounds seem to be promising against paraoxon-inhibited AChE. Better results were obtained for bisquaternary substances at least with one oxime group in position four. None of tested substances was able to satisfactorily reactivate tabun-inhibited AChE at concentration applicable for in vivo experiments.
ESTHER : Musilek_2006_Bioorg.Med.Chem.Lett_16_5673
PubMedSearch : Musilek_2006_Bioorg.Med.Chem.Lett_16_5673
PubMedID: 16934462

Title : Synthesis of the novel series of bispyridinium compounds bearing (E)-but-2-ene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase - Musilek_2006_Bioorg.Med.Chem.Lett_16_622
Author(s) : Musilek K , Kuca K , Jun D , Dohnal V , Dolezal M
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :622 , 2006
Abstract : Six potential AChE reactivators were synthesized using modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by insecticide chlorpyrifos was tested in vitro. According to the results, (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-e ne dibromide seems to be the most potent AChE reactivator. The reactivation potency of these compounds depends on structural factors such as constitution of the linking chain between both pyridinium rings, position of the oxime moiety at the pyridinium ring and presence of quaternary nitrogens.
ESTHER : Musilek_2006_Bioorg.Med.Chem.Lett_16_622
PubMedSearch : Musilek_2006_Bioorg.Med.Chem.Lett_16_622
PubMedID: 16288867

Title : Strategy for the development of new acetylcholinesterase reactivators - antidotes used for treatment of nerve agent poisonings - Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_429
Author(s) : Kuca K , Cabal J , Jun D , Kassa J , Bartosova L , Kunesova G , Dohnal V
Ref : Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub , 149 :429 , 2005
Abstract : The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents, is based on the formation of irreversibly inhibited acetylcholinesterase (AChE; EC 3.1.1.7) that could be followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic drug (atropine mostly) to counteract the accumulation of acetylcholine at muscarinic receptors and AChE reactivators (pralidoxime or obidoxime) to reactivate inhibited AChE. At the Department of Toxicology, the strategy of the development of new more potent AChE reactivators consists of several steps: description of the nerve agent intoxication mechanism on the molecular basis (molecular design), prediction of the biological active structure of AChE reactivators (artificial neural networks), their synthesis, in vitro evaluation of their potencies (potentiometric titration and Ellman's method), in vivo studies (therapeutic index, LD(50) of newly synthesized reactivators, reactivation in different tissues, neuroprotective efficacy).
ESTHER : Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_429
PubMedSearch : Kuca_2005_Biomed.Pap.Med.Fac.Univ.Palacky.Olomouc.Czech.Repub_149_429
PubMedID: 16601804

Title : Synthesis of a novel series of bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against chlorpyrifos-inhibited acetylcholinesterase - Musilek_2005_J.Enzyme.Inhib.Med.Chem_20_409
Author(s) : Musilek K , Kuca K , Jun D , Dohnal V , Dolezal M
Ref : J Enzyme Inhib Med Chem , 20 :409 , 2005
Abstract : Nine potential AChE reactivators were synthesized using a modification of currently known synthetic pathways. Their potency to reactivate AChE inhibited by insecticide chlorpyrifos was tested in vitro. 2,2'-Bis(hydroxyiminomethyl)-1,1'-(1,4-phenylenedimethyl)-bispyridinium dibromide seems to be the most potent AChE reactivator. The reactivation potency of these compounds depends on structural factors such as length of the linking chain between both pyridinium rings and position of the oxime moiety on the pyridinium ring.
ESTHER : Musilek_2005_J.Enzyme.Inhib.Med.Chem_20_409
PubMedSearch : Musilek_2005_J.Enzyme.Inhib.Med.Chem_20_409
PubMedID: 16335048

Title : 1,3-Bis(2-hydroxyiminomethylpyridinium) propane as the potential reactivator of the acetylcholinesterase inhibited by nerve agents - Kuca_2004_Acta.Medica.(Hradec.Kralove)_47_167
Author(s) : Kuca K , Dohnal V
Ref : Acta Medica (Hradec Kralove) , 47 :167 , 2004
Abstract : The oxime K005 [1,3-bis(2-hydroxyiminomethylpyridinium) propane dibromide] for the reactivation of the enzyme acetylcholinesterase (AChE) inhibited by cyclosarin and VX was tested. Its reactivation potency was not better in comparison with the currently used AChE reactivator--pralidoxime. On the other hand, the oxime K005 has its maximum reactivation ability at the concentration 10(-4) M, which could be achieved for human use. The maximum concentration of pralidoxime was reached at the concentrations 10(-1) M (for cyclosarin) and 10(-3) M (for VX) but these concentrations are not available for the use in vivo.
ESTHER : Kuca_2004_Acta.Medica.(Hradec.Kralove)_47_167
PubMedSearch : Kuca_2004_Acta.Medica.(Hradec.Kralove)_47_167
PubMedID: 15568733

Title : Cyclodextrines as functional agents for decontamination of the skin contaminated by nerve agents - Cabal_2004_Acta.Medica.(Hradec.Kralove)_47_115
Author(s) : Cabal J , Kuca K , Sevelova-Bartosova L , Dohnal V
Ref : Acta Medica (Hradec Kralove) , 47 :115 , 2004
Abstract : Three decontamination solutions of beta-cyclodextrines were prepared. Their abilities to decontamine rat skin contamined with nerve agent soman were tested. Decontamination efficacy of the tested cyclodextrine solutions was compared with the same decontamination means but without the cyclodextrines. The efficacy of tested decontaminants was evaluated by the assessment of the ID50 values. Two decontamination prescriptions with cyclodextrines (tetraborate buffer and tetraborate buffer with acetone) do not show significantly better decontamination efficacies in comparison with prescriptions without cyclodextrines. Only in case of aqueous solution of 2-aminoethanol the addition of beta-cyclodextrine resulted in significant increase (32%) in decontamination efficacy.
ESTHER : Cabal_2004_Acta.Medica.(Hradec.Kralove)_47_115
PubMedSearch : Cabal_2004_Acta.Medica.(Hradec.Kralove)_47_115
PubMedID: 15446361