Jost P


Full name : Jost Petr

First name : Petr

Mail : Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01,\; Biomedical Research Centre, University Hospital, Sokolska 581, 500 05, Hradec Kralove

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Country : Czech Republic

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References (17)

Title : Differentiated SH-SY5Y neuroblastoma cells as a model for evaluation of nerve agent-associated neurotoxicity - Pulkrabkova_2023_Arch.Toxicol__
Author(s) : Pulkrabkova L , Muckova L , Hrabinova M , Sorf A , Kobrlova T , Jost P , Bezdekova D , Korabecny J , Jun D , Soukup O
Ref : Archives of Toxicology , : , 2023
Abstract : Organophosphorus compounds (OPs) involving life-threatening nerve agents (NA) have been known for several decades. Despite a clear mechanism of their lethality caused by the irreversible inhibition of acetylcholinesterase (AChE) and manifested via overstimulation of peripheral nicotinic and muscarinic acetylcholine (ACh) receptors, the mechanism for central neurotoxicity responsible for acute or delayed symptoms of the poisoning has not been thoroughly uncovered. One of the reasons is the lack of a suitable model. In our study, we have chosen the SH-SY5Y model in both the differentiated and undifferentiated state to study the effects of NAs (GB, VX and A234). The activity of expressed AChE in cell lysate assessed by Ellman's method showed 7.3-times higher activity in differentiated SH-SY5Y cells in contrast to undifferentiated cells, and with no involvement of BuChE as proved by ethopropazine (20 microM). The activity of AChE was found to be, in comparison to untreated cells, 16-, 9.3-, and 1.9-times lower upon A234, VX, and GB (100 microM) administration respectively. The cytotoxic effect of given OPs expressed as the IC(50) values for differentiated and undifferentiated SH-SY5Y, respectively, was found 12 mM and 5.7 mM (A234), 4.8 mM and 1.1 mM (VX) and 2.6 mM and 3.8 mM (GB). In summary, although our results confirm higher AChE expression in the differentiated SH-SY5Y cell model, the such higher expression does not lead to a more pronounced NA cytotoxic effect. On the contrary, higher expression of AChE may attenuate NA-induced cytotoxicity by scavenging the NA. Such finding highlights a protective role for cholinesterases by scavenging Novichoks (A-agents). Second, we confirmed the mechanism of cytotoxicity of NAs, including A-agents, can be ascribed rather to the non-specific effects of OPs than to AChE-mediated effects.
ESTHER : Pulkrabkova_2023_Arch.Toxicol__
PubMedSearch : Pulkrabkova_2023_Arch.Toxicol__
PubMedID: 37221426

Title : Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimes drugs dealing with cholinergic, amyloid and mitochondrial systems - Nepovimova_2020_Bioorg.Chem_107_104596
Author(s) : Nepovimova E , Svobodova L , Dolezal R , Hepnarova V , Junova L , Jun D , Korabecny J , Kucera T , Gazova Z , Motykova K , Kubackova J , Bednarikova Z , Janockova J , Jesus C , Cortes L , Pina J , Rostohar D , Serpa C , Soukup O , Aitken L , Hughes RE , Musilek K , Muckova L , Jost P , Chvojkova M , Vales K , Valis M , Chrienova Z , Chalupova K , Kuca K
Ref : Bioorg Chem , 107 :104596 , 2020
Abstract : A series of tacrine - benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid beta (Abeta) aggregation and mitochondrial enzyme ABAD, whose interaction with Abeta leads to mitochondrial dysfunction, into a single molecule. In vitro, several of 25 final compounds exerted excellent anti-AChE properties and interesting capabilities to block Abeta aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC(50) value in nanomolar range. Moreover, the same drug candidate exerted absolutely the best results of the series against ABAD, decreasing its activity by 23% at 100 microM concentration. Regarding the cytotoxicity profile of highlighted compound, it roughly matched that of its parent compound - 6-chlorotacrine. Finally, 10w was forwarded for in vivo scopolamine-induced amnesia experiment consisting of Morris Water Maze test, where it demonstrated mild procognitive effect. Taking into account all in vitro and in vivo data, highlighted derivative 10w could be considered as the lead structure worthy of further investigation.
ESTHER : Nepovimova_2020_Bioorg.Chem_107_104596
PubMedSearch : Nepovimova_2020_Bioorg.Chem_107_104596
PubMedID: 33421953

Title : Encapsulation of oxime K027 into cucurbit[7]uril: In vivo evaluation of safety, absorption, brain distribution and reactivation effectiveness - Karasova_2020_Toxicol.Lett_320_64
Author(s) : Karasova JZ , Hepnarova V , Andrys R , Lisa M , Jost P , Muckova L , Pejchal J , Herman D , Jun D , Kassa J , Kuca K
Ref : Toxicol Lett , 320 :64 , 2020
Abstract : Oxime-based acetylcholinesterase reactivators (briefly oximes) regenerate organophosphate-inactivated acetylcholinesterase and restore its function. Poor blood-brain-barrier passage and fast elimination from blood limit their actual use in treatment of patients exposed to organophosphates. Previous in vitro results implicated further testing of cucurbit[7]uril as a delivery vehicle for bisquaternary oximes. The present paper focuses on cell toxicity, in vivo safety and influence of cucurbit[7]uril on oxime pharmacokinetics and pharmacodynamics. Neither the K027 nor the complex caused any cell toxicity, changes in blood biochemistry or hepato- or nephrotoxicity in tested concentrations. The encapsulation of K027 increased and accelerated the blood-brain-barrier penetration. The peripheral oxime exposure also increased, supporting the suggestion that cucurbit[7]uril protects the circulating oxime from rapid renal clearance. Contrary to the comparable in vitro reactivation power of K027 and the encapsulated K027, we failed to confirm this in vivo. In theory, this might result from the non-specific binding of molecules to the cucurbit[7]uril or the interaction of K027 with cucurbit[7]uril being too strong for acetylcholinesterase reactivation. Precise explanation requires additional in silico, in vitro and also in vivo experiments.
ESTHER : Karasova_2020_Toxicol.Lett_320_64
PubMedSearch : Karasova_2020_Toxicol.Lett_320_64
PubMedID: 31794810

Title : Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease - Chalupova_2019_Eur.J.Med.Chem_168_491
Author(s) : Chalupova K , Korabecny J , Bartolini M , Monti B , Lamba D , Caliandro R , Pesaresi A , Brazzolotto X , Gastellier AJ , Nachon F , Pejchal J , Jarosova M , Hepnarova V , Jun D , Hrabinova M , Dolezal R , Karasova JZ , Mzik M , Kristofikova Z , Misik J , Muckova L , Jost P , Soukup O , Benkova M , Setnicka V , Habartova L , Chvojkova M , Kleteckova L , Vales K , Mezeiova E , Uliassi E , Valis M , Nepovimova E , Bolognesi ML , Kuca K
Ref : Eur Journal of Medicinal Chemistry , 168 :491 , 2019
Abstract : A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC50 values of 6.3 and 9.1nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Abeta42 self-aggregation (58.6+/-5.1% at 50muM) as well as hAChE-induced Abeta40 aggregation (48.3+/-6.3% at 100muM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.
ESTHER : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedSearch : Chalupova_2019_Eur.J.Med.Chem_168_491
PubMedID: 30851693
Gene_locus related to this paper: torca-ACHE

Title : N-alkylated Tacrine Derivatives as Potential Agents in Alzheimer's Disease Therapy - Nepovimova_2019_Curr.Alzheimer.Res_16_333
Author(s) : Nepovimova E , Korabecny J , Hepnarova V , Jun D , Dolezal R , Muckova L , Jost P , Soukup O , Janockova J , Pham NL , Nguyen TD , Valis M , Kuca K
Ref : Curr Alzheimer Res , 16 :333 , 2019
Abstract : BACKGROUND: Based on the prevalence studies, the number of people suffering from dementia will almost double every 20 years, to 65.7 million in 2030 and 115.4 million in 2050, assuming no changes in mortality, effective preventative measures, definitive diagnostic guidelines or curative treatment. From the abovementioned epidemiological data, it is obvious that dementia constitutes a major public health problem not only at present, but unfortunately also in the future. OBJECTIVES AND METHODS: Several N-alkylated tacrine (THA) derivatives have already been synthesized by Pomponi et al., in 1997. However, these compounds were tested for their anti-AChE activity using enzyme isolated from Electrophorus electricus. For this reason, we have decided to extend the previously reported series of THA derivatives and consequently test them in the battery of experiments, the results of which have served to more relevant evaluation of these compounds from the perspective of Alzeimer s disease compared to that published by Pomponi. RESULTS AND CONCLUSION: In summary, all compounds of interest effectively inhibited ChEs in vitro. One of the most promising derivatives 8 bearing an N-octyl chain showed 2.5-fold higher AChE inhibitory activity in relation to tacrine. With respect to blood-brain barrier (BBB) penetration, it can be claimed that synthesized analogues are presumably able to cross the BBB. From the point of view of hepatotoxicity, selected Nalkylated tacrine derivatives exerted worse results compared to tacrine. However, in vitro results are only illustrative, therefore, only in vivo experiments could determine the real value of selected N-alkylated THA derivatives.
ESTHER : Nepovimova_2019_Curr.Alzheimer.Res_16_333
PubMedSearch : Nepovimova_2019_Curr.Alzheimer.Res_16_333
PubMedID: 30873921

Title : The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease - Hepnarova_2018_Eur.J.Med.Chem_150_292
Author(s) : Hepnarova V , Korabecny J , Matouskova L , Jost P , Muckova L , Hrabinova M , Vykoukalova N , Kerhartova M , Kucera T , Dolezal R , Nepovimova E , Spilovska K , Mezeiova E , Pham NL , Jun D , Staud F , Kaping D , Kuca K , Soukup O
Ref : Eur Journal of Medicinal Chemistry , 150 :292 , 2018
Abstract : Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50=74.5nM; hBChE IC50=83.3nM) with micromolar antagonistic activity towards M1 mAChR (IC50=4.23muM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.
ESTHER : Hepnarova_2018_Eur.J.Med.Chem_150_292
PubMedSearch : Hepnarova_2018_Eur.J.Med.Chem_150_292
PubMedID: 29533874

Title : In vitro and in silico Evaluation of Non-Quaternary Reactivators of AChE as Antidotes of Organophosphorus Poisoning - a New Hope or a Blind Alley? - Soukup_2018_Med.Chem_14_281
Author(s) : Soukup O , Korabecny J , Malinak D , Nepovimova E , Pham NL , Musilek K , Hrabinova M , Hepnarova V , Dolezal R , Pavek P , Jost P , Kobrlova T , Jankockova J , Gorecki L , Psotka M , Nguyen TD , Box K , Outhwaite B , Ceckova M , Sorf A , Jun D , Kuca K
Ref : Med Chem , 14 :281 , 2018
Abstract : BACKGROUND: In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. OBJECTIVE: In this study, we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. METHODS: This time, we used only in silico prediction and in vitro approaches. RESULTS: Our data showed that tested uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. CONCLUSION: From the presented data, it seems that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.
ESTHER : Soukup_2018_Med.Chem_14_281
PubMedSearch : Soukup_2018_Med.Chem_14_281
PubMedID: 29332594

Title : Cytotoxicity of acetylcholinesterase reactivators evaluated in vitro and its relation to their structure - Muckova_2018_Drug.Chem.Toxicol__1
Author(s) : Muckova L , Pejchal J , Jost P , Vanova N , Herman D , Jun D
Ref : Drug & Chemical Toxicology , :1 , 2018
Abstract : The development of acetylcholinesterase reactivators, i.e., antidotes against organophosphorus poisoning, is an important goal of defense research. The aim of this study was to compare cytotoxicity and chemical structure of five currently available oximes (pralidoxime, trimedoxime, obidoxime, methoxime, and asoxime) together with four perspective oximes from K-series (K027, K074, K075, and K203). The cytotoxicity of tested substances was measured using two methods - colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay and impedance based real-time cytotoxicity assay - in three different cell lines (HepG2, ACHN, and NHLF). Toxicity was subsequently expressed as toxicological index IC50. The tested compounds showed different cytotoxicity ranging from 0.92 to 40.06 mM. In HepG2 cells, K027 was the least and asoxime was the most toxic reactivator. In ACHN and NHLF cell lines, trimedoxime was the compound with the lowest adverse effects, whereas the highest toxicity was found in methoxime-treated cells. The results show that at least five structural features affect the reactivators' toxicity such as the number of oxime groups in the molecule, their position on pyridinium ring, the length of carbon linker, and the oxygen substitution or insertion of the double bond into the connection chain. Newly synthetized oximes with IC50 >/= 1 mM evaluated in this three cell lines model might appear suitable for further testing.
ESTHER : Muckova_2018_Drug.Chem.Toxicol__1
PubMedSearch : Muckova_2018_Drug.Chem.Toxicol__1
PubMedID: 29421945

Title : Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation - Spilovska_2017_Molecules_22_
Author(s) : Spilovska K , Korabecny J , Sepsova V , Jun D , Hrabinova M , Jost P , Muckova L , Soukup O , Janockova J , Kucera T , Dolezal R , Mezeiova E , Kaping D , Kuca K
Ref : Molecules , 22 : , 2017
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 muM). 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.
ESTHER : Spilovska_2017_Molecules_22_
PubMedSearch : Spilovska_2017_Molecules_22_
PubMedID: 28621747

Title : Development of 2-Methoxyhuprine as Novel Lead for Alzheimer's Disease Therapy - Mezeiova_2017_Molecules_22_
Author(s) : Mezeiova E , Korabecny J , Sepsova V , Hrabinova M , Jost P , Muckova L , Kucera T , Dolezal R , Misik J , Spilovska K , Pham NL , Pokrievkova L , Roh J , Jun D , Soukup O , Kaping D , Kuca K
Ref : Molecules , 22 : , 2017
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.
ESTHER : Mezeiova_2017_Molecules_22_
PubMedSearch : Mezeiova_2017_Molecules_22_
PubMedID: 28788095

Title : Multi-target-directed therapeutic potential of 7-methoxytacrine-adamantylamine heterodimers in the Alzheimer's disease treatment - Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
Author(s) : Gazova Z , Soukup O , Sepsova V , Siposova K , Drtinova L , Jost P , Spilovska K , Korabecny J , Nepovimova E , Fedunova D , Horak M , Kaniakova M , Wang ZJ , Hamouda AK , Kuca K
Ref : Biochimica & Biophysica Acta Mol Basis Dis , 1863 :607 , 2017
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 beta-secretase (BACE1) activity, Abeta 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 Abeta 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.
ESTHER : Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
PubMedSearch : Gazova_2017_Biochim.Biophys.Acta.Mol.Basis.Dis_1863_607
PubMedID: 27865910

Title : Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease - Benek_2016_ChemMedChem_11_1264
Author(s) : Benek O , Soukup O , Pasdiorova M , Hroch L , Sepsova V , Jost P , Hrabinova M , Jun D , Kuca K , Zala D , Ramsay RR , Marco-Contelles J , Musilek K
Ref : ChemMedChem , 11 :1264 , 2016
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 mum), butyrylcholinesterase (BChE IC50 : 2.4 mum) and MAO A (IC50 : 0.49 mum), and it is also a weak inhibitor of MAO B (IC50 : 53.9 mum). Although its cytotoxic (IC50 : 5.5+/-0.4 mum) and hepatotoxic (IC50 : 1.22+/-0.11 mum) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63+/-4 and 11.50+/-0.77 mum, 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.
ESTHER : Benek_2016_ChemMedChem_11_1264
PubMedSearch : Benek_2016_ChemMedChem_11_1264
PubMedID: 26427608

Title : A 7-methoxytacrine-4-pyridinealdoxime hybrid as a novel prophylactic agent with reactivation properties in organophosphate intoxication - Nepovimova_2016_Toxicol.Res.(Camb)_5_1012
Author(s) : Nepovimova E , Korabecny J , Dolezal R , Nguyen TD , Jun D , Soukup O , Pasdiorova M , Jost P , Muckova L , Malinak D , Gorecki L , Musilek K , Kuca K
Ref : Toxicol Res (Camb) , 5 :1012 , 2016
Abstract : Chemical warfare agents constitute an increasing threat to both military and civilian populations. Therefore, effective prophylactic approaches are urgently needed. Herein, we present a novel hybrid compound which is able not only to keep acetylcholinesterase resistant to organophosphate (OP) inhibitors, but also to serve as an enzyme reactivator in the case of OP intoxication.
ESTHER : Nepovimova_2016_Toxicol.Res.(Camb)_5_1012
PubMedSearch : Nepovimova_2016_Toxicol.Res.(Camb)_5_1012
PubMedID: 30090408

Title : Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity - Nepovimova_2015_J.Med.Chem_58_8985
Author(s) : Nepovimova E , Korabecny J , Dolezal R , Babkova K , Ondrejicek A , Jun D , Sepsova V , Horova A , Hrabinova M , Soukup O , Bukum N , Jost P , Muckova L , Kassa J , Malinak D , Andrs M , Kuca K
Ref : Journal of Medicinal Chemistry , 58 :8985 , 2015
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.
ESTHER : Nepovimova_2015_J.Med.Chem_58_8985
PubMedSearch : Nepovimova_2015_J.Med.Chem_58_8985
PubMedID: 26503905

Title : Cytotoxicity and genotoxicity evaluation of antidote oxime HI-6 tested on eight cell lines of human and rodent origin - Svobodova_2012_Gen.Physiol.Biophys_31_77
Author(s) : Svobodova H , Jost P , Stetina R
Ref : Gen Physiol Biophys , 31 :77 , 2012
Abstract : Oxime HI-6 is an efficient reactivator of the acetylcholinesterase inhibited by organophosphorous nerve agents. In this study we have estimated cytotoxicity of HI-6 by the colony forming assay and genotoxicity by the comet assay on human and rodent cell lines. IC50 of HI-6 assessed by the colony forming capacity was 3.59 mM for HeLa cells and 5.18 mM for a mouse cell line L929. Small difference in cytotoxicity was found among other cell lines tested: IC50 was 1.61 mM for human A549 cells, 1.14 mM for UROtse line, 1.96 mM and 1.71 mM for Chinese hamster cells AA8 and UV-20, respectively. The A549 cell viability measured with the MTT test was 5 times decreased comparing 2 and 24 hours of HI-6 oxime treatment. The 5 mM HI-6 concentration reduced the viability within 2 hours to 95% only, however, it induced a significant number of DNA breaks in mouse cells L929, and also in human UROtse and HepG2 cells. 1-beta-D-arabinofuranosylcytosine (10(-4) M) and hydroxyurea (10(-2) M), supplemented to the cultivation medium, did not cause any significant accumulation of DNA breaks during treatment, which indicated that the nucleotide excision repair was not acting on the induced DNA damage.
ESTHER : Svobodova_2012_Gen.Physiol.Biophys_31_77
PubMedSearch : Svobodova_2012_Gen.Physiol.Biophys_31_77
PubMedID: 22447833

Title : Comparison of potential cytotoxicity and genotoxicity of selected antidotes against organophosphates inhibiting acetylcholinesterase - Svobodova_2011_Mil.Med.Sci.Lett_80_142
Author(s) : Svobodova H , Jost P , Stetina R
Ref : Military Medical Science Letters , 80 :142 , 2011
Abstract : Organophosphorous compounds cause fatal intoxication based on inhibition of acetylcholinesterase, an essential enzyme of neurosynapses and neuromuscular junctions. There is an obvious need to develop appropriate treatment against them due to their application in agriculture and chemical industry or their misuse in terrorist or war attack.In the Czech army some medicaments have been established to be used against this poisoning; Obidoxime, Methoxime, Atropine and Benactyzine. In present in vitro study we focused on potential cytotoxic and genotoxic effect evaluation of these drugs by the clonogenic and comet assay, respectively.Obtained results show that oximes exhibit pronounced toxic effect, namely obidoxime in term of genotoxicity and methoxime in term of cytotoxicity.
ESTHER : Svobodova_2011_Mil.Med.Sci.Lett_80_142
PubMedSearch : Svobodova_2011_Mil.Med.Sci.Lett_80_142

Title : Photosuicide inactivation of acetylcholinesterase by nitrosamine derivatives - Eid_1981_Biochemistry_20_2251
Author(s) : Eid P , Goeldner M , Hirth C , Jost P
Ref : Biochemistry , 20 :2251 , 1981
Abstract : Methyl(acetoxymethyl)nitrosamine and methyl-(butyroxymethyl)nitrosamine are respectively substrate KM 10(-2 M and competitive inhibitor Ki 2 x 10(-3 M of electric eel acetylcholinesterase EC Irradiation of an incubation mixture of this enzyme with either nitrosamine leads to an irreversible loss of enzyme activity The inactivation rates are dependent on photolysis wavelength light intensity and inhibitor concentration Experiments where acetylcholinesterase was radioactively labeled by 14C methyl(acetoxymethyl)nitrosamine show that the incorporation of 1 mol of radioactive label per active site is sufficient to cause complete enzyme inactivation irrespective of the reaction conditions used Methyl(acetoxymethyl)nitrosamine shows no affinity while methyl(butyroxymethyl)nitrosamine is a competitive inhibitor Ki 2 x 10(-3 M but no irreversible inhibition is induced by the action of light We propose that a suicide type of inhibition Bloch K 1969 Acc Chem Res 2 193-198 is responsible for the inactivation of acetylcholinesterase based on photoactivation of nitrosamines only when associated with an acidic hydrogen of the active site
ESTHER : Eid_1981_Biochemistry_20_2251
PubMedSearch : Eid_1981_Biochemistry_20_2251
PubMedID: 7236595