159 results on '"Daniel Jun"'
Search Results
2. Design and synthesis of novel tacrine–indole hybrids as potential multitarget-directed ligands for the treatment of Alzheimer's disease
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Vendula Hepnarova, Slavka Hamulakova, Jan Korabecny, Ondrej Soukup, Roman Mezencev, Ladislav Janovec, Martina Hrabinova, Veronika Ihnatova, Yury O. Chernoff, Zachery J. Deckner, Nikola Novakova, Zuzana Kudličková, Kamil Kuca, Petr Bzonek, Jana Janockova, and Daniel Jun
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Indoles ,Stereochemistry ,Drug Evaluation, Preclinical ,Molecular Dynamics Simulation ,Ligands ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Molecular Targeted Therapy ,7-methoxytacrine ,Biological evaluation ,Pharmacology ,Indole test ,Amyloid beta-Peptides ,Chemistry ,DNA ,In vitro ,Molecular Docking Simulation ,Neuroprotective Agents ,Blood-Brain Barrier ,Tacrine ,Acetylcholinesterase ,Molecular Medicine ,Cholinesterase Inhibitors ,Dimerization ,Protein Binding ,Research Article ,medicine.drug - Abstract
The authors report on the synthesis and biological evaluation of new compounds whose structure combines tacrine and indole moieties. Tacrine–indole heterodimers were designed to inhibit cholinesterases and β-amyloid formation, and to cross the blood–brain barrier. The most potent new acetylcholinesterase inhibitors were compounds 3c and 4d (IC50 = 25 and 39 nM, respectively). Compound 3c displayed considerably higher selectivity for acetylcholinesterase relative to human plasma butyrylcholinesterase in comparison to compound 4d (selectivity index: IC50 [butyrylcholinesterase]/IC50 [acetylcholinesterase] = 3 and 0.6, respectively). Furthermore, compound 3c inhibited β-amyloid-dependent amyloid nucleation in the yeast-based prion nucleation assay and displayed no dsDNA destabilizing interactions with DNA. Compounds 3c and 4d displayed a high probability of crossing the blood–brain barrier. The results support the potential of 3c for future development as a dual-acting therapeutic agent in the prevention and/or treatment of Alzheimer's disease.
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- 2021
3. Synthesis, in vitro screening and molecular docking of isoquinolinium-5-carbaldoximes as acetylcholinesterase and butyrylcholinesterase reactivators
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Daniel Jun, Eva Mezeiova, Rudolf Andrys, Jan Korabecny, Lukas Gorecki, Kamil Musilek, David Malinak, Miroslava Hozova, Veronika Racakova, Petr Bzonek, Kamil Kuca, Miroslav Psotka, Vendula Hepnarova, and Rafael Dolezal
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Cholinesterase Reactivators ,Stereochemistry ,organophosphate ,RM1-950 ,01 natural sciences ,oxime ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Butyrylcholinesterase ,Cholinesterase ,Pharmacology ,biology ,010405 organic chemistry ,Organophosphate ,General Medicine ,Oxime ,Isoquinolines ,Acetylcholinesterase ,In vitro ,0104 chemical sciences ,reactivator ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,chemistry ,biology.protein ,Therapeutics. Pharmacology ,Cholinesterase Inhibitors ,Research Paper - Abstract
The series of symmetrical and unsymmetrical isoquinolinium-5-carbaldoximes was designed and prepared for cholinesterase reactivation purposes. The novel compounds were evaluated for intrinsic acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) inhibition, when the majority of novel compounds resulted with high inhibition of both enzymes and only weak inhibitors were selected for reactivation experiments on human AChE or BChE inhibited by sarin, VX, or paraoxon. The AChE reactivation for all used organophosphates was found negligible if compared to the reactivation ability of obidoxime. Importantly, two compounds were found to reactivate BChE inhibited by sarin or VX better to obidoxime at human attainable concentration. One compound resulted as better reactivator of NEMP (VX surrogate)-inhibited BChE than obidoxime. The in vitro results were further rationalized by molecular docking studies showing future directions on designing potent BChE reactivators., GRAPHICAL ABSTRACT
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- 2020
4. Amaryllidaceae Alkaloids of Norbelladine-Type as Inspiration for Development of Highly Selective Butyrylcholinesterase Inhibitors: Synthesis, Biological Activity Evaluation, and Docking Studies
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Ondřej Soukup, Filip Pidaný, Rozálie Peřinová, Lubica Muckova, Jiří Kuneš, Tomas Kucera, Abdullah Al Mamun, Negar Maafi, Jan Korábečný, Rudolf Andrýs, Monika Schmidt, Jiří Janoušek, Martina Hrabinova, Jana Maříková, Lucie Cahlíková, Daniela Hulcová, Daniel Jun, Lucie Nováková, and Maria Carmen Catapano
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Pharmacology ,01 natural sciences ,chemistry.chemical_compound ,Neuroblastoma ,Tumor Cells, Cultured ,Biology (General) ,Spectroscopy ,Butyrylcholinesterase ,0303 health sciences ,biology ,Biological activity ,General Medicine ,Receptor antagonist ,Acetylcholinesterase ,Computer Science Applications ,Molecular Docking Simulation ,Chemistry ,Alzheimer’s disease ,medicine.drug_class ,QH301-705.5 ,Tyramine ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Structure-Activity Relationship ,medicine ,Humans ,Computer Simulation ,Physical and Theoretical Chemistry ,Amaryllidaceae Alkaloids ,norbelladine-type ,Molecular Biology ,IC50 ,QD1-999 ,amaryllidaceae alkaloid ,030304 developmental biology ,Cholinesterase ,Cell Proliferation ,010405 organic chemistry ,Organic Chemistry ,docking studies ,0104 chemical sciences ,chemistry ,Docking (molecular) ,biology.protein ,Cholinesterase Inhibitors - Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative condition of the central nervous system (CNS) that is currently treated by cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist, memantine. Emerging evidence strongly supports the relevance of targeting butyrylcholinesterase (BuChE) in the more advanced stages of AD. Within this study, we have generated a pilot series of compounds (1–20) structurally inspired from belladine-type Amaryllidaceae alkaloids, namely carltonine A and B, and evaluated their acetylcholinesterase (AChE) and BuChE inhibition properties. Some of the compounds exhibited intriguing inhibition activity for human BuChE (hBuChE), with a preference for BuChE over AChE. Seven compounds were found to possess a hBuChE inhibition profile, with IC50 values below 1 µM. The most potent one, compound 6, showed nanomolar range activity with an IC50 value of 72 nM and an excellent selectivity pattern over AChE, reaching a selectivity index of almost 1400. Compound 6 was further studied by enzyme kinetics, along with in-silico techniques, to reveal the mode of inhibition. The prediction of CNS availability estimates that all the compounds in this survey can pass through the blood-brain barrier (BBB), as disclosed by the BBB score.
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- 2021
5. Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells
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Daniel Jun, Monika Hudáčová, Juraj Ševc, Jana Vargová, Jana Janockova, Mária Kožurková, Veronika Ihnatova, Jan Korábečný, Petr Bzonek, Lucie Junova, Nikola Novakova, Eva Konkoľová, Kamil Kuca, Ondrej Soukup, Rastislav Jendželovský, Slávka Hamuľaková, Peter Fedoročko, and Tomas Kucera
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0301 basic medicine ,Models, Molecular ,Chemistry Techniques, Synthetic ,Pharmacology ,blood–brain barrier ,lcsh:Chemistry ,chemistry.chemical_compound ,0302 clinical medicine ,A549 ,Coumarins ,lcsh:QH301-705.5 ,Spectroscopy ,Butyrylcholinesterase ,Molecular Structure ,Cell Cycle ,General Medicine ,Cell cycle ,Acetylcholinesterase ,Computer Science Applications ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Alzheimer’s disease ,antiproliferative activity ,cholinesterase ,Cell Survival ,Antineoplastic Agents ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Structure-Activity Relationship ,Alzheimer Disease ,Humans ,MTT assay ,Physical and Theoretical Chemistry ,Molecular Biology ,A549 cell ,biscoumarin ,Dose-Response Relationship, Drug ,Cell growth ,Organic Chemistry ,In vitro ,Enzyme Activation ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,A549 Cells ,Cancer cell ,Cholinesterase Inhibitors - Abstract
A series of novel C4-C7-tethered biscoumarin derivatives (12a–e) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC50 = 6.30 µM) and butyrylcholinesterase (BChE, IC50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE (hAChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e. The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of hAChE/human recombinant BChE (hBChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.
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- 2021
6. (±)- BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3β Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease
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Vendula Hepnarova, Kamil Musilek, Aurélie Baguet, Daniel Jun, José Marco-Contelles, Lhassane Ismaili, Emmanuel Haffen, Tomas Kucera, Jan Korabecny, Jana Janockova, Angela De Simone, Eva M. García-Frutos, Vincenza Andrisano, Manuela Bartolini, B. Refouvelet, Lucía Viejo, Cristóbal de los Ríos, Adeline Etievant, Ondrej Soukup, Rudolf Andrys, Julie Monnin, Raquel L Arribas, Conseil régional of Franche-Comté, Czech Science Foundation, Ministry of Education, Youth and Sports (Czech Republic), Ismaili L., Monnin J., Etievant A., Arribas R.L., Viejo L., Refouvelet B., Soukup O., Janockova J., Hepnarova V., Korabecny J., Kucera T., Jun D., Andrys R., Musilek K., Baguet A., Garcia-Frutos E.M., De Simone A., Andrisano V., Bartolini M., De Los Rios C., Marco-Contelles J., and Haffen E.
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cholinesterase ,Physiology ,Monoamine oxidase ,Cognitive Neuroscience ,Ligand ,Pharmacology ,Ligands ,Calcium Channel ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,In vivo ,GSK-3 ,Humans ,Cholinesterases ,Cholinesterase Inhibitor ,Biginelli reaction ,Alzheimer's disease ,calcium channel ,cholinesterases ,GSK 3β ,MAO ,Calcium Channel Blockers ,Calcium Channels ,Cholinesterase Inhibitors ,Glycogen Synthase Kinase 3 beta ,Monoamine Oxidase ,GSK3B ,030304 developmental biology ,Cholinesterase ,0303 health sciences ,Voltage-dependent calcium channel ,biology ,Chemistry ,Calcium channel ,Cell Biology ,General Medicine ,Calcium channel, GSK 3β, MAO ,biology.protein ,Monoamine oxidase A ,Calcium Channel Blocker ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Human - Abstract
Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3β and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and β-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits., L.I. thanks the Regional Council of Franche-Comté (2016YC- 04540 and 04560) for financial support, Mrs. M.-J. Henriot (PHV Pharma) for her support in the HPLC analyses, and Vincent Luzet for preliminary results in synthesis. O.S., J.J., and J.K. acknowledge the support from the grant by Czech Science Foundation no. 20-29633J. T.K., D.J., and V.H. acknowledge support from the Long-term Development Plan (Faculty of Military Health Sciences). R.A. and K.M. thank the Ministry of Education, Youth and Sports of the Czech Republic (ERDF no. CZ.02.1.01/0.0/0.0/16_025/0007444).
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- 2021
7. Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
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José A. Dias, Tereza Kobrlova, Vendula Hepnarova, Tomas Kucera, Daniel Jun, Lubica Muckova, Florian Nachon, David Malinak, Jan Korabecny, Kamil Musilek, Franz Worek, Martina Hrabinova, Lukas Gorecki, Ondrej Soukup, Charlotte Courageux, Jana Zdarova Karasova, and Lukas Prchal
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0301 basic medicine ,Male ,Cholinesterase Reactivators ,Health, Toxicology and Mutagenesis ,Antidotes ,010501 environmental sciences ,Pharmacology ,Molecular Dynamics Simulation ,Toxicology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Oximes ,medicine ,Animals ,Butyrylcholinesterase ,0105 earth and related environmental sciences ,Tabun ,Nerve agent ,Mice, Inbred BALB C ,General Medicine ,Acetylcholinesterase ,In vitro ,Acute toxicity ,030104 developmental biology ,chemistry ,Toxicity ,Female ,medicine.drug - Abstract
To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.
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- 2020
8. Tacrine - Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems
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Jana Janockova, Jana Kubackova, Karel Vales, Petr Jost, João Pina, Zuzana Bednarikova, Jan Korabecny, Katarina Motykova, Eugenie Nepovimova, Luísa Cortes, Zofia Chrienova, Kamil Musilek, Carlos Serpa, Rafael Dolezal, Lucie Svobodova, Lucie Junova, Laura Aitken, Vendula Hepnarova, Martin Vališ, Katarina Chalupova, Ondrej Soukup, Danijela Rostohar, Marketa Chvojkova, Daniel Jun, Lubica Muckova, Catarina S. H. Jesus, Zuzana Gazova, Kamil Kuca, Rebecca E. Hughes, and Tomas Kucera
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Amyloid ,Cholinergic Agents ,Pharmacology ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Protein Aggregates ,Structure-Activity Relationship ,In vivo ,Alzheimer Disease ,Drug Discovery ,medicine ,Humans ,Benzothiazoles ,Enzyme Inhibitors ,Molecular Biology ,IC50 ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,3-Hydroxyacyl CoA Dehydrogenases ,Acetylcholinesterase ,In vitro ,0104 chemical sciences ,Mitochondria ,010404 medicinal & biomolecular chemistry ,Neuroprotective Agents ,Benzothiazole ,chemistry ,Tacrine ,Cholinergic ,medicine.drug - Abstract
A series of tacrine – benzothiazole hybrids incorporate inhibitors of acetylcholinesterase (AChE), amyloid β (Aβ) aggregation and mitochondrial enzyme ABAD, whose interaction with Aβ 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 Aβ aggregation. The best derivative of the series could be considered 10w that was found to be highly potent and selective towards AChE with the IC50 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 µM 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.
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- 2020
9. Is It the Twilight of BACE1 Inhibitors?
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Martina Hrabinova, Daniel Jun, Ondrej Soukup, Jaroslav Pejchal, Monika Schmidt, and Tomas Kucera
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Amyloid beta ,Skin rashes ,Disease ,Bioinformatics ,Placebo ,Weight loss ,Alzheimer Disease ,Aricle ,mental disorders ,inhibitors ,Medicine ,Aspartic Acid Endopeptidases ,Humans ,β-secretase ,Pharmacology (medical) ,Prospective Studies ,Adverse effect ,substrates ,Pharmacology ,clinical trials ,Amyloid beta-Peptides ,biology ,business.industry ,General Medicine ,Clinical trial ,amyloid beta ,Psychiatry and Mental health ,Neurology ,β secretase ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Amyloid Precursor Protein Secretases ,business ,Alzheimer’s disease - Abstract
β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.
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- 2020
10. Pharmacological prophylaxis against nerve agent poisoning: experimental studies and practical implications
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Josef Fusek, Daniel Jun, Kamil Kuca, Jiri Bajgar, and Jiri Kassa
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Benactyzine ,Chemistry ,medicine.medical_treatment ,Organophosphate ,Pharmacology ,Acetylcholinesterase ,chemistry.chemical_compound ,Pyridostigmine ,Detoxification ,medicine ,Antidote ,Butyrylcholinesterase ,medicine.drug ,Nerve agent - Abstract
Prophylaxis against intoxication with organophosphate (OP) nerve agents is based on various approaches. Protection of acetylcholinesterase (AChE), the target enzyme for toxic action of OP nerve agents, is a basic requirement for effective prophylaxis. This can be achieved by using reversible AChE inhibitors, preferably carbamates (CMs). AChE inhibited by CMs is resistant to the action of an OP nerve agent for a transient period. After spontaneous recovery of the activity, normal AChE serves as a source of the active enzyme. Detoxification is carried out by the administration of enzymes hydrolyzing the OPs or evaluating specific enzymes (cholinesterases). The OP nerve agent is bound to the exogenously administered enzyme, and thus the OP level in the organism is decreased (“scavenger” effect). The administration of enzymes, such as AChE and butyrylcholinesterase, as scavengers seems to be very promising, as the enzyme acts at the very beginning of the toxic action, and without interaction with target tissues and without side effects. The antidotes currently used for the treatment of OP poisoning can be tested as prophylactics. This principle can be considered as a treatment in advance. Standard antidotes were studied in this respect; that is, anticholinergics, enzyme reactivators, anticonvulsants, and others. The problem with their use is the timing, duration, and achievement of sufficient levels of these antidotes after administration. At present, pyridostigmine seems to be a common prophylactic antidote, while PANPAL (tablets with pyridostigmine, trihexyphenidyle, and benactyzine) and TRANSANT (a transdermal patch containing HI-6) are the prophylactics. Future drug development will be focused on scavengers (cholinesterases and other enzymes) acting prior to the binding of the nerve agent to the target sites, and to other drugs either reversible cholinesterase inhibitors (e.g., huperzine A, physostigmine, acridine derivatives, etc.) or other compounds.
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- 2020
11. Oxime K033-Reactivation Activity of Cholinesterases Inhibited by Various Nerve Agents and Organophosphorus Pesticides
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Kamil Musilek, Ondrej Krejcar, Ondrej Soukup, Qinghua Wu, Daniel Jun, Teodorico C. Ramalho, Raquel O. Lopes, Jaroslav Pejchal, Tanos C. C. França, Marek Penhaker, Eugenie Nepovimova, and Kamil Kuca
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biology ,Chemistry ,medicine.medical_treatment ,010401 analytical chemistry ,Pharmaceutical Science ,04 agricultural and veterinary sciences ,Pharmacology ,Pesticide ,Oxime ,040401 food science ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,0404 agricultural biotechnology ,Drug Discovery ,medicine ,biology.protein ,Molecular Medicine ,Antidote ,Organophosphorus pesticides ,Nerve agent ,medicine.drug ,Cholinesterase - Published
- 2018
12. Oxime K074 – in vitro and in silico reactivation of acetylcholinesterase inhibited by nerve agents and pesticides
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Alexandre A. de Castro, Eugenie Nepovimova, Elaine F. F. da Cunha, Ondrej Krejcar, Kamil Kuca, Tanos C. C. França, Teodorico C. Ramalho, Ondrej Soukup, Jan Korabecny, Kamil Musilek, and Daniel Jun
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021110 strategic, defence & security studies ,Aché ,medicine.medical_treatment ,In silico ,0211 other engineering and technologies ,02 engineering and technology ,010501 environmental sciences ,Pesticide ,Pharmacology ,Toxicology ,Oxime ,01 natural sciences ,Acetylcholinesterase ,language.human_language ,In vitro ,chemistry.chemical_compound ,chemistry ,medicine ,language ,Antidote ,0105 earth and related environmental sciences ,Nerve agent ,medicine.drug - Abstract
Oxime K074 was formerly considered to be a lead structure for design of novel oximes for reactivation of tabun-inhibited acetylcholinesterase (AChE). In this study, we are summarizing its reactivat...
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- 2018
13. Reactivation Potential of Novel More Lipophilic Pralidoxime Analogs
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Jan Misik, Daniel Jun, Martina Hrabinova, and Kamil Kuca
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Pralidoxime ,Chemistry ,Drug Discovery ,medicine ,Pharmaceutical Science ,Molecular Medicine ,Pharmacology ,medicine.drug - Published
- 2018
14. The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease
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Eugenie Nepovimova, Ondřej Soukup, Tomas Kucera, Daniel Kaping, Ngoc Lam Pham, Katarina Spilovska, Daniel Jun, L. Matouskova, M. Kerhartova, Eva Mezeiova, Lubica Muckova, Petr Jost, Kamil Kuca, Vendula Hepnarova, Frantisek Staud, Martina Hrabinova, Jan Korabecny, Rafael Dolezal, and N. Vykoukalova
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0301 basic medicine ,Stereochemistry ,Carboxylic acid ,Cell Line ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,0302 clinical medicine ,Alzheimer Disease ,Drug Discovery ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Humans ,Moiety ,Butyrylcholinesterase ,Cholinesterase ,Pharmacology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,General Medicine ,Acetylcholinesterase ,030104 developmental biology ,chemistry ,Docking (molecular) ,Tacrine ,Quinolines ,biology.protein ,Cholinesterase Inhibitors ,030217 neurology & neurosurgery ,medicine.drug - 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 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 μM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.
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- 2018
15. Oxidative stress in organophosphate poisoning: role of standard antidotal therapy
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Jaroslav Pejchal, David Herman, Daniel Jun, Alzbeta Dlabkova, and Nela Vanova
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0301 basic medicine ,business.industry ,medicine.drug_class ,Organophosphate ,Pharmacology ,Toxicology ,medicine.disease_cause ,medicine.disease ,Acetylcholinesterase ,Organophosphate poisoning ,03 medical and health sciences ,chemistry.chemical_compound ,Atropine ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Toxicity ,medicine ,Anticholinergic ,business ,030217 neurology & neurosurgery ,Oxidative stress ,Nerve agent ,medicine.drug - Abstract
Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration.
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- 2018
16. Development of small bisquaternary cholinesterase inhibitors as drugs for pre-treatment of nerve agent poisonings
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Eva Novotná, Martin Vališ, Kamil Kuca, Ondrej Soukup, Jaroslav Pejchal, Eva Vodakova, Kamil Musilek, Jana Zdarova Karasova, Daniel Jun, Vendula Sepsova, Jiri Kassa, Anna Horova, Martina Hrabinova, and Eugenie Nepovimova
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Models, Molecular ,0301 basic medicine ,Cell Survival ,Pharmaceutical Science ,Pharmacology ,AChE inhibitors ,nerve agents ,Cell Line ,Small Molecule Libraries ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Drug Discovery ,Soman ,medicine ,Humans ,Original Research ,Nerve agent ,Cholinesterase ,Drug Design, Development and Therapy ,soman ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,toxicity ,pre-treatment ,Acetylcholinesterase ,Acute toxicity ,030104 developmental biology ,chemistry ,Pyridostigmine ,Toxicity ,biology.protein ,prophylaxis ,Cholinesterase Inhibitors ,030217 neurology & neurosurgery ,HeLa Cells ,medicine.drug - Abstract
Kamil Kuca,1,2 Jana Zdarova Karasova,2,3 Ondrej Soukup,2 Jiri Kassa,3 Eva Novotna,2 Vendula Sepsova,2,3 Anna Horova,2 Jaroslav Pejchal,3 Martina Hrabinova,2,3 Eva Vodakova,2 Daniel Jun,2,3 Eugenie Nepovimova,1,2 Martin Valis,4 Kamil Musilek1,2 1Department of Chemistry, Faculty of Science, University of Hradec Kralove, 2Biomedical Research Center, University Hospital Hradec Kralove, 3Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, 4Department of Neurology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic 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. Keywords: AChE inhibitors, prophylaxis, pre-treatment, nerve agents, toxicity, soman
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- 2018
17. Cytotoxicity of acetylcholinesterase reactivators evaluated in vitro and its relation to their structure
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David Herman, Lubica Muckova, Petr Jost, Jaroslav Pejchal, Daniel Jun, and Nela Vanova
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Obidoxime ,Cholinesterase Reactivators ,Pralidoxime ,Cell Survival ,Health, Toxicology and Mutagenesis ,Chemical structure ,Drug Evaluation, Preclinical ,010501 environmental sciences ,Animal Testing Alternatives ,Toxicology ,01 natural sciences ,Lethal Dose 50 ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oximes ,medicine ,Humans ,Trimedoxime ,Cytotoxicity ,0105 earth and related environmental sciences ,Pharmacology ,Chemical Health and Safety ,Molecular Structure ,Public Health, Environmental and Occupational Health ,Hep G2 Cells ,General Medicine ,Fibroblasts ,Oxime ,Acetylcholinesterase ,Combinatorial chemistry ,chemistry ,Toxicity ,030217 neurology & neurosurgery ,medicine.drug - 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.
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- 2018
18. A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase
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Teodorico C. Ramalho, Martina Hrabinova, Elaine F. F. da Cunha, Martin Vališ, Tanos C. C. França, Kamil Musilek, John Mikler, Alexandre A. de Castro, Ondrej Soukup, Eugenie Nepovimova, Daniel Jun, Jana Zdarova-Karasova, and Kamil Kuca
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0301 basic medicine ,Obidoxime ,Cholinesterase Reactivators ,Pralidoxime ,Aché ,Antidotes ,Chemical warfare agents ,Pyridinium Compounds ,Pharmacology ,01 natural sciences ,Oxime ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,lcsh:RA1190-1270 ,Oximes ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Cholinesterase ,Tabun ,lcsh:Toxicology. Poisons ,biology ,Poisoning ,010401 analytical chemistry ,Reactivator ,lcsh:RM1-950 ,Brain ,Acetylcholinesterase ,language.human_language ,Organophosphates ,0104 chemical sciences ,Rats ,Molecular Docking Simulation ,Treatment ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,chemistry ,biology.protein ,language ,Cholinesterase Inhibitors ,medicine.drug ,Research Article - Abstract
Background Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. Methods To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). Results Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (k r) of 2142 min− 1. M− 1, which was 51 times higher than that obtained for obidoxime (k r = 42 min− 1. M− 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. Discussion According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.
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- 2018
19. The influence of modulators of acetylcholinesterase on the resistance of mice against soman and on the effectiveness of antidotal treatment of soman poisoning in mice
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Daniel Jun, Jiri Kassa, Eugenie Nepovimova, and Jan Korabecny
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0301 basic medicine ,Health, Toxicology and Mutagenesis ,Biomedical Engineering ,Pharmacology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Artificial Intelligence ,6-chlorotacrine ,Soman ,medicine ,Potency ,General Pharmacology, Toxicology and Pharmaceutics ,General Immunology and Microbiology ,General Neuroscience ,General Medicine ,Oxime ,Acetylcholinesterase ,Acute toxicity ,Atropine ,030104 developmental biology ,chemistry ,General Agricultural and Biological Sciences ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The potency of one reversible inhibitor of acetylcholinesterase (6-chlorotacrine), one reactivator of acetycholinesterase (K027) and their combination to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. While 6-chlorotacrine was able to markedly protect mice against acute toxicity of soman and the pharmacological pretreatment with 6-chlorotacrine increased the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice more than two times, the bispyridinium oxime K027 did not protect mice from acute toxicity of soman, however, the pharmacological pretreatment with this compound was able to markedly increase the efficacy of antidotal treatment of soman-poisoned mice. On the other hand, the combination of both modulators of acetylcholinesterase did not increase the prophylactic efficacy of 6-chlorotacrine alone. These findings demonstrate that pharmacological pretreatment of soman-poisoned mice can be promising and useful in the case of administration of 6-chlorotacrine while the administration of the oxime K027 did not bring any additional benefit when combined with 6-chlorotacrine.
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- 2018
20. Profiling donepezil template into multipotent hybrids with antioxidant properties
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Jana Janockova, Ondrej Soukup, Katarina Spilovska, Eugenie Nepovimova, Eva Mezeiova, Jan Korabecny, Rafael Dolezal, Kamil Kuca, David Malinak, Daniel Jun, and Lukas Gorecki
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0301 basic medicine ,Antioxidant ,medicine.medical_treatment ,multi-target directed ligands ,Review Article ,Pharmacology ,medicine.disease_cause ,Antioxidants ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Piperidines ,Alzheimer Disease ,mental disorders ,Drug Discovery ,medicine ,Humans ,oxidative stress ,Donepezil ,Rivastigmine ,Molecular Structure ,business.industry ,lcsh:RM1-950 ,General Medicine ,Acetylcholinesterase ,donepezil ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,Indans ,Cholinesterase Inhibitors ,business ,Alzheimer’s disease ,Oxidative stress ,medicine.drug - Abstract
Alzheimer’s disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer’s disease.
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- 2018
21. HLö-7 - A REVIEW OF ACETYLCHOLINESTERASE REACTIVATOR AGAINST ORGANOPHOSPHOROUS INTOXICATION
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Daniel Jun, Jan Korábečný, Ondřej Soukup, Thuy Duong Nguyen, Kamil Kuca, Kamil Musilek, Lukas Gorecki, Maliňák David, and Miroslav Psotka
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0301 basic medicine ,Emergency Medical Services ,Veterinary (miscellaneous) ,Public Health, Environmental and Occupational Health ,Pharmacology ,Acetylcholinesterase ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Immunology and Microbiology (miscellaneous) ,chemistry ,030220 oncology & carcinogenesis ,Emergency Medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Published
- 2017
22. Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment
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Gunnar Tobin, Michael Winder, Vladimír Wsól, Kamil Kuca, Ondrej Soukup, Daniel Jun, and Uday Kumar Killi
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0301 basic medicine ,Pharmacology ,Article ,03 medical and health sciences ,pharmacotherapy ,0302 clinical medicine ,Muscarinic acetylcholine receptor ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,Receptor ,business.industry ,muscarinic receptor subtypes ,Muscarinic acetylcholine receptor M3 ,Muscarinic acetylcholine receptor M2 ,General Medicine ,acetylcholinesterase ,Receptor Cross-Talk ,Receptors, Muscarinic ,Acetylcholine ,Psychiatry and Mental health ,030104 developmental biology ,Nicotinic agonist ,Neurology ,Cholinergic ,Neurology (clinical) ,Cholinesterase Inhibitors ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Pharmaceuticals with targets in the cholinergic transmission have been used for decades and are still fundamental treatments in many diseases and conditions today. Both the transmission and the effects of the somatomotoric and the parasympathetic nervous systems may be targeted by such treatments. Irrespective of the knowledge that the effects of neuronal signalling in the nervous systems may include a number of different receptor subtypes of both the nicotinic and the muscarinic receptors, this complexity is generally overlooked when assessing the mechanisms of action of pharmaceuticals. Methods We have search of bibliographic databases for peer-reviewed research literature focused on the cholinergic system. Also, we have taken advantage of our expertise in this field to deduce the conclusions of this study. Results Presently, the life cycle of acetylcholine, muscarinic receptors and their effects are reviewed in the major organ systems of the body. Neuronal and non-neuronal sources of acetylcholine are elucidated. Examples of pharmaceuticals, in particular cholinesterase inhibitors, affecting these systems are discussed. The review focuses on salivary glands, the respiratory tract and the lower urinary tract, since the complexity of the interplay of different muscarinic receptor subtypes is of significance for physiological, pharmacological and toxicological effects in these organs. Conclusion Most pharmaceuticals targeting muscarinic receptors are employed at such large doses that no selectivity can be expected. However, some differences in the adverse effect profile of muscarinic antagonists may still be explained by the variation of expression of muscarinic receptor subtypes in different organs. However, a complex pattern of interactions between muscarinic receptor subtypes occurs and needs to be considered when searching for selective pharmaceuticals. In the development of new entities for the treatment of for instance pesticide intoxication, the muscarinic receptor selectivity needs to be considered. Reactivators generally have a muscarinic M2 receptor acting profile. Such a blockade may engrave the situation since it may enlarge the effect of the muscarinic M3 receptor effect. This may explain why respiratory arrest is the major cause for deaths by esterase blocking.
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- 2017
23. Bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors: in vitro screening of probes for novel selective insecticides
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Lenka Matouskova, Rafael Dolezal, Tomas Kucera, Kamil Kuca, Lukas Gorecki, Jan Korabecny, Brigita Manyova, Kamil Musilek, Veronika Hrabcova, Eugenie Nepovimova, and Daniel Jun
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0301 basic medicine ,chemistry.chemical_classification ,Aché ,General Chemical Engineering ,General Chemistry ,Pharmacology ,Pesticide ,Acetylcholinesterase ,language.human_language ,In vitro ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Enzyme ,chemistry ,Biochemistry ,Docking (molecular) ,Toxicity ,language ,Pyridinium - Abstract
Insects have a huge impact on quality of life around the world. They play roles in transmitting diseases, crop-destruction, and as residential pests. Their increased resistance to the existing pesticides and the toxicity of carbamates (CA) and organophosphates (OP) has led to the development of new environmentally safe insecticides. In our study, thirty different bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors were tested as candidates for potential new selective pesticides. Our compounds were evaluated in vitro on insect acetylcholinesterase (AChE) from Musca domestica and human erythrocyte AChE using the modified Ellman's method. The values of IC50 were compared and expressed via a selectivity index (SI) towards the insect enzyme. K299, K416, and K423 provided a high SI and seem to be suitable as new lead structures of novel selective anticholinesterase insecticides. Docking studies further provided the rational background uncovering the disparities in the ligand–enzyme binding modes for each AChE enzyme. In vitro assessments as well as docking studies highlighted K299 and K416 as suitable candidates for lead structures of novel pesticides. However, further evaluation is needed to confirm this statement.
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- 2017
24. Encapsulation of oxime K027 into cucurbit[7]uril: In vivo evaluation of safety, absorption, brain distribution and reactivation effectiveness
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Miroslav Lísa, Daniel Jun, Jana Zdarova Karasova, Jaroslav Pejchal, Petr Jost, Kamil Kuca, Rudolf Andrys, Lubica Muckova, David Herman, Vendula Hepnarova, and Jiri Kassa
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0301 basic medicine ,Bridged-Ring Compounds ,Male ,Sarin ,Cholinesterase Reactivators ,Erythrocytes ,Maximum Tolerated Dose ,Cell Survival ,Pyridinium Compounds ,Pharmacology ,Toxicology ,GPI-Linked Proteins ,Injections, Intramuscular ,Risk Assessment ,Nephrotoxicity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,In vivo ,Oximes ,Animals ,Humans ,Tissue Distribution ,Actual use ,Mice, Inbred ICR ,Dose-Response Relationship, Drug ,Imidazoles ,Brain ,General Medicine ,Hep G2 Cells ,Oxime ,Acetylcholinesterase ,In vitro ,030104 developmental biology ,chemistry ,A549 Cells ,Female ,030217 neurology & neurosurgery - 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.
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- 2019
25. Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease
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Daniel Jun, Vendula Hepnarova, Eva Mezeiova, Martin Mzik, Karel Vales, Lubica Muckova, Michaela Jarosova, Lenka Kleteckova, Alessandro Pesaresi, Jana Zdarova Karasova, Vladimír Setnička, Rafael Dolezal, Florian Nachon, Petr Jost, Jan Misik, Rosanna Caliandro, Martina Hrabinova, Doriano Lamba, Anne-Julie Gastellier, Zdena Kristofikova, Xavier Brazzolotto, Marketa Chvojkova, Martin Vališ, Lucie Habartová, Jaroslav Pejchal, Marketa Benkova, Jan Korabecny, Maria Laura Bolognesi, Ondrej Soukup, Katarina Chalupova, Barbara Monti, Manuela Bartolini, Kamil Kuca, Elisa Uliassi, Eugenie Nepovimova, Chalupova K., Korabecny J., Bartolini M., Monti B., Lamba D., Caliandro R., Pesaresi A., Brazzolotto X., Gastellier A.-J., Nachon F., Pejchal J., Jarosova M., Hepnarova V., Jun D., Hrabinova M., Dolezal R., Zdarova Karasova J., 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 M.L., and Kuca K.
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Male ,Amyloid beta-Peptide ,hAChEinduced Aβ40 aggregation ,Pharmacology ,Ligands ,01 natural sciences ,chemistry.chemical_compound ,Tacrine-tryptophan hybrids ,Drug Discovery ,Cholinesterase Inhibitor ,Butyrylcholinesterase ,Blood-brain barrier ,0303 health sciences ,Molecular Structure ,Chemistry ,Abeta42 self-aggregation ,Tryptophan ,Multi-target directed ligands ,General Medicine ,Alzheimer's disease ,Acetylcholinesterase ,X-ray crystallographic analysi ,Neuroprotective Agents ,Aβ42 self-aggregation ,Tacrine ,Toxicity ,Tacrine-tryptophan hybrid ,Pharmacophore ,Human ,medicine.drug ,Neuroprotective Agent ,Ligand ,Protein Aggregates ,Structure-Activity Relationship ,03 medical and health sciences ,Alzheimer Disease ,medicine ,Animals ,Humans ,Multi-target directed ligand ,Potency ,Rats, Wistar ,Maze Learning ,030304 developmental biology ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Animal ,010405 organic chemistry ,Organic Chemistry ,Rats ,0104 chemical sciences ,X-ray crystallographic analysis ,Rat ,Protein Aggregate ,Cholinesterase Inhibitors ,Enantiomer ,hAChE induced Abeta40 aggregation - 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 9.1 nM, 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 Aβ42 self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ40 aggregation (48.3 ± 6.3% at 100 μM). 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.
- Published
- 2019
26. Isoquinoline alkaloids from berberis vulgaris as potential lead compounds for the treatment of alzheimer's disease
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Vincenza Andrisano, Daniel Jun, Jan Korabecny, Jana Marikova, Daniel I. Perez, Lucie Nováková, Tomas Kucera, Lucie Cahlíková, Tomáš Siatka, Jiri Kunes, Daniela Hulcová, Lubomír Opletal, Anna Hošt'álková, Hostalkova A., Marikova J., Opletal L., Korabecny J., Hulcova D., Kunes J., Novakova L., Perez D.I., Jun D., Kucera T., Andrisano V., Siatka T., and Cahlikova L.
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Berberis ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Plant Exudates ,Pharmaceutical Science ,Oligopeptidase ,Berbamine ,01 natural sciences ,Analytical Chemistry ,chemistry.chemical_compound ,Alkaloids ,Alzheimer Disease ,Drug Discovery ,Humans ,Isoquinoline ,IC50 ,Butyrylcholinesterase ,Pharmacology ,010405 organic chemistry ,Organic Chemistry ,Isoquinoline alkaloids, lead compounds, alzheimer's disease ,Nuclear magnetic resonance spectroscopy ,Isoquinolines ,Acetylcholinesterase ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,chemistry ,Blood-Brain Barrier ,Molecular Medicine ,Cholinesterase Inhibitors ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Three new alkaloids, bersavine (3), muraricine (4), and berbostrejdine (8), together with seven known isoquinoline alkaloids (1-2, 5-7, 9, and 10) were isolated from an alkaloidal extract of the root bark of Berberis vulgaris. The structures of the isolated compounds were determined by spectroscopic methods, including 1D and 2D NMR techniques, HRMS, and optical rotation, and by comparison of the obtained data with those in the literature. The NMR data of berbamine (5), aromoline (6), and obamegine (7) were completely assigned employing 2D NMR experiments. Alkaloids isolated in sufficient amounts were evaluated for their in vitro acetylcholinesterase, butyrylcholinesterase (BuChE), prolyl oligopeptidase, and glycogen synthase kinase-3β inhibitory activities. Selected compounds were studied for their ability to permeate through the blood-brain barrier. Significant human BuChE ( hBuChE) inhibitory activity was demonstrated by 6 (IC50 = 0.82 ± 0.10 μM). The in vitro data were further supported by computational analysis that showed the accommodation of 6 in the active site of hBuChE.
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- 2019
27. Pursuing the Complexity of Alzheimer’s Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists
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Tomas Kucera, Daniel Jun, Lenka Pulkrabkova, Marketa Benkova, Stepan Kortus, Vladimir Finger, Marharyta Kolcheva, Martina Hrabinova, Jan Konecny, Tereza Kobrlova, Ondrej Soukup, Jan Korabecny, Martin Horak, Anna Misiachna, Lukas Prchal, and Marian Valko
- Subjects
In silico ,multi-target directed ligands ,lcsh:QR1-502 ,Pharmacology ,Biochemistry ,lcsh:Microbiology ,N-methyl-d-aspartate receptor ,fluorene ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Receptor ,Molecular Biology ,Butyrylcholinesterase ,030304 developmental biology ,Cholinesterase ,0303 health sciences ,biology ,Chemistry ,in vitro ,acetylcholinesterase ,Acetylcholinesterase ,in silico ,Docking (molecular) ,Tacrine ,butyrylcholinesterase ,biology.protein ,NMDA receptor ,Alzheimer’s disease ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Alzheimer&rsquo, s disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood&ndash, brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
- Published
- 2020
28. The wide-spectrum antimicrobial effect of novel N-alkyl monoquaternary ammonium salts and their mixtures; the QSAR study against bacteria
- Author
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Aneta Markova, Nina Gunde-Cimerman, Marketa Benkova, Michaela Hympanova, Sarka Salajkova, Vanda Boštíková, Ondrej Soukup, Jan Marek, Daniel Jun, Pavel Boštík, Kristina Sepčić, David Malinak, Radek Sleha, Lukas Prchal, Rafael Dolezal, Lenka Ryskova, Jan Korabecny, and Lenka Hobzova
- Subjects
Alkylation ,Heteroatom ,Quantitative Structure-Activity Relationship ,Microbial Sensitivity Tests ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Anti-Infective Agents ,Drug Discovery ,Humans ,Molecule ,Ammonium ,Alkyl ,Skin ,030304 developmental biology ,Pharmacology ,chemistry.chemical_classification ,0303 health sciences ,biology ,010405 organic chemistry ,Organic Chemistry ,General Medicine ,Antimicrobial ,biology.organism_classification ,Combinatorial chemistry ,0104 chemical sciences ,Quaternary Ammonium Compounds ,chemistry ,Lipophilicity ,Antibacterial activity ,Bacteria - Abstract
Quaternary ammonium salts (QASs) have been widely used for disinfection purposes because of their low price, high efficacy and low human toxicity for decades. However, precise mechanisms of action nor the powerful versatile agent against all antimicrobial species are known. In this study we have prepared 43 novel N-alkyl monoquaternary ammonium salts including 7 N,N-dialkyl monoquaternary ammonium salts differing bearing alkyl chain either of 12, 14 or 16 carbons. Together with 15 already published QASs we have studied the antimicrobial efficacy of all water-soluble compounds together with standard benzalkonium salts against Gram-positive (G+) and Gram-negative (G-) bacteria, anaerobic spore-forming Cl. difficile, yeasts, filamentous fungi and enveloped Varicella zoster virus (VZV). To address the mechanism of action, lipophilicity seems to be a key parameter which determines antimicrobial efficacy, however, exceptions are likely to occur and therefore QSAR analysis on the efficacy against G+ and G- bacteria was applied. We showed that antibacterial activity is higher when the molecule is larger, more lipophilic, less polar, and contains fewer oxygen atoms, fewer methyl groups bound to heteroatoms or fewer hydrogen atoms bound to polarized carbon atoms. In addition, from an application point of view, we have formulated mixtures, on the basis of obtained efficiency of individual compounds, in order to receive wide-spectrum agent. All formulated mixtures completely eradicated tested G+ and G- strains, including the multidrug-resistant P. aeruginosa as well as in case of yeasts. However, effect on A. fumigatus, Cl. difficile and VZV the exposition towards mixture resulted in significant reduction only. Finally, 3 out of 4 formulated mixtures were safer than reference commercial agent based on benzalkonium salts only in the skin irritation test using reconstructed human epidermidis.
- Published
- 2020
29. SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides
- Author
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Daniel Jun, Jan Korabecny, Kamil Musilek, Rafael Dolezal, Eugenie Nepovimova, Kamil Kuca, David Malinak, Ondrej Soukup, and Lukas Gorecki
- Subjects
0301 basic medicine ,Cholinesterase Reactivators ,Sarin ,Protein Conformation ,Health, Toxicology and Mutagenesis ,Antidotes ,Molecular Conformation ,Pyridinium Compounds ,Pharmacology ,Ligands ,Toxicology ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,Organophosphate Poisoning ,Organophosphorus Compounds ,0302 clinical medicine ,Catalytic Domain ,Soman ,medicine ,Animals ,Humans ,Pesticides ,Nerve agent ,Tabun ,Binding Sites ,Molecular Structure ,Paraoxon ,Chemistry ,Organophosphate ,General Medicine ,Acetylcholinesterase ,030104 developmental biology ,Drug Design ,030220 oncology & carcinogenesis ,Chlorpyrifos ,Cholinesterase Inhibitors ,Nerve Agents ,medicine.drug - Abstract
Irreversible inhibition of acetylcholinesterase (AChE) by organophosphates leads to many failures in living organism and ultimately in death. Organophosphorus compounds developed as nerve agents such as tabun, sarin, soman, VX and others belong to the most toxic chemical warfare agents and are one of the biggest threats to the modern civilization. Moreover, misuse of nerve agents together with organophosphorus pesticides (e.g. malathion, paraoxon, chlorpyrifos, etc.) which are annually implicated in millions of intoxications and hundreds of thousand deaths reminds us of insufficient protection against these compounds. Basic treatments for these intoxications are based on immediate administration of atropine and acetylcholinesterase reactivators which are currently represented by mono- or bis-pyridinium aldoximes. However, these antidotes are not sufficient to ensure 100 % treatment efficacy even they are administered immediately after intoxication, and in general, they possess several drawbacks. Herein, we have reviewed new efforts leading to the development of novel reactivators and proposition of new promising strategies to design novel and effective antidotes. Structure-activity relationships and biological activities of recently proposed acetylcholinesterase reactivators are discussed and summarized. Among further modifications of known oximes, the main attention has been paid to dual binding site ligands of AChE as the current mainstream strategy. We have also discussed new chemical entities as potential replacement of oxime functional group.
- Published
- 2016
30. Small Molecules Targeting Ataxia Telangiectasia and Rad3-Related (ATR) Kinase: An Emerging way to Enhance Existing Cancer Therapy
- Author
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Martin Andrs, Kamil Kuca, Eugenie Nepovimova, Jan Korabecny, Daniel Jun, and Zdenek Hodny
- Subjects
Cancer Research ,DNA damage ,DNA repair ,Ataxia Telangiectasia Mutated Proteins ,Biology ,Small Molecule Libraries ,Ataxia Telangiectasia ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Drug Discovery ,medicine ,Ultraviolet light ,Humans ,030212 general & internal medicine ,Pharmacology ,Kinase ,medicine.disease ,Oncology ,Biochemistry ,030220 oncology & carcinogenesis ,Ataxia-telangiectasia ,Cancer cell ,Cancer research ,Ataxia telangiectasia and Rad3 related ,Signal Transduction - Abstract
The main aim of current cancer research is to find a way to selectively affect the tumor cells, while leaving normal cells intact. Ataxia telangiectasia and Rad3-related kinase (ATR), a member of the phosphatidylinositol-3-related protein kinases (PIKK), represents a candidate target for achieving this goal. ATR kinase is one of the main kinases of the DNA damage response signaling pathway and responds to DNA damage caused by replication stress and various genotoxic agents (i.e. chemotherapy, ionizing radiation, ultraviolet light). ATR activation triggers cell cycle checkpoints, DNA repair and apoptosis, but also resistance of tumor cells to DNA damaging agents, through stress support under replication stress. Thus, the inhibition of ATR leads to increased effectiveness of cancer therapy and in addition enables highly selective targeting of cancer cells through synthetic lethal interactions. Despite this great potential, only a few potent and selective inhibitors of ATR kinase have been developed to date. However, those which have been developed provide great promise, and are under evaluation in many current preclinical and clinical trials. The purpose of this review is to summarize the potential of ATR inhibitors and the medicinal chemistry efforts which resulted in their identification.
- Published
- 2016
31. Novel caffeine derivatives with antiproliferative activity
- Author
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Pavel Siman, Rafael Dolezal, Martina Seifrtova, Martin Andrs, Kamil Kuca, Ondrej Benek, Ondrej Soukup, Jan Korabecny, Daniel Jun, Darina Muthna, and Martina Rezacova
- Subjects
0301 basic medicine ,DNA damage ,Kinase ,DNA repair ,General Chemical Engineering ,General Chemistry ,Cell cycle ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Cancer cell ,Phosphatidylinositol ,Protein kinase A ,Caffeine - Abstract
Caffeine is probably the best known and most widely used psychoactive substance in the world. Beside its psychoactive effects, caffeine has been found to affect the cell cycle and DNA repair, as a consequence of the inhibition of ATM and ATR kinases. These two DNA damage response kinases, members of the phosphatidylinositol 3-kinase related protein kinase family, represent very attractive anticancer drug targets. Their inhibition can selectively sensitize cancer cells to DNA damaging agents and even kill various tumour cells in monotherapy. We developed a series of caffeine derivatives and evaluated their antiproliferative effects on 11 human tumour cell lines and compared them against caffeine and a standard ATR inhibitor VE-821. Although the new caffeine derivatives did not achieve the overall potency of VE-821, several compounds exhibited enhanced antiproliferative activity compared to caffeine and in some cell lines showed at least comparable activity to VE-821.
- Published
- 2016
32. Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile
- Author
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Martina Hrabinova, Jana Janockova, Lukas Prchal, Marketa Benkova, Ondrej Soukup, Ondrej Benek, Eva Mezeiova, Daniel Jun, Katerina Sobolova, Vendula Hepnarova, Jan Korabecny, Rafael Dolezal, Tereza Kobrlova, and Tomas Kucera
- Subjects
Quantitative structure–activity relationship ,Berberine ,Amyloid beta ,Oligopeptidase ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Line, Tumor ,Drug Discovery ,Cholinesterases ,Humans ,Cytotoxicity ,Butyrylcholinesterase ,030304 developmental biology ,Pharmacology ,0303 health sciences ,biology ,010405 organic chemistry ,Organic Chemistry ,General Medicine ,Acetylcholinesterase ,0104 chemical sciences ,chemistry ,Biochemistry ,Blood-Brain Barrier ,Docking (molecular) ,Drug Design ,biology.protein ,Cholinesterase Inhibitors ,Prolyl Oligopeptidases - Abstract
Berberine, a naturally occurring compound, possesses an interesting multipotent pharmacological profile potentially applicable for Alzheimer’s disease (AD) treatment. In this study, a series of novel 22 berberine derivatives was developed and tested in vitro. Berberine core was substituted at position 9-O of its aromatic ring region. All the hybrids under the study revealed multi-targeted profile inhibiting prolyl oligopeptidase, acetylcholinesterase and butyrylcholinesterase highlighting 4a, 4g, 4j, 4l and 4s possessing balanced activities in the micromolar range. The top-ranked candidates in terms of the most pronounced potency against POP, AChE and BChE can be classified as 4d, 4u and 4v, bearing 4-methylbenzyl, (naphthalen-2-yl)methylene and 1-phenoxyethyl moieties, respectively. In vitro data were corroborated by detailed kinetic analysis of the selected lead molecules. 4d, 4u and 4v were also inspected for their potential to inhibit aggregation of two abberant proteins in AD, namely amyloid beta and tau, indicating their potential disease-modifying properties. To explain the results of our study, we carried out docking simulation to the active sites of the respective enzyme with the best berberine derivatives, along with QSAR study. We also investigated compounds’ potential permeability through blood-brain barrier by applying parallel artificial membrane permeation assay and addressed their cytotoxicity profile.
- Published
- 2020
33. Purin-6-one and pyrrolo[2,3-d]pyrimidin-4-one derivatives as potentiating agents of doxorubicin cytotoxicity
- Author
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Martin Andrs, Katerina Vejrychova, Lukas Gorecki, Ales Tichy, Radim Havelek, Martina Rezacova, Jan Korabecny, Martina Seifrtova, Monika Pospisilova, Daniel Jun, and Michaela Polednikova
- Subjects
0301 basic medicine ,Purinones ,DNA damage ,medicine.medical_treatment ,Antineoplastic Agents ,Pyrimidinones ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,medicine ,Humans ,Doxorubicin ,LY294002 ,In patient ,Pyrroles ,Cytotoxicity ,Cell Proliferation ,Pharmacology ,Radiation therapy ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Molecular Medicine ,Conventional chemotherapy ,medicine.drug - Abstract
Aim: DNA damage response plays an eminent role in patients’ response to conventional chemotherapy and radiotherapy. Its inhibition is of great interest as it can overcome cancer cell resistance and reduce the effective doses of DNA damaging agents. Results & methodology: We have focused our research on phosphatidylinositol 3-kinase-related kinases and prepared 35 novel compounds through a scaffold hopping approach. The newly synthesized inhibitors were tested on a panel of nine cancer and one healthy cell lines alone and in combination with appropriate doses of doxorubicin. Conclusion: Five novel compounds 4f, 10b, 15g, 7e and 15f in combination with doxorubicin showed significant antiproliferative effect on seven cancer cell lines while not affecting the cell growth alone.
- Published
- 2018
34. N-alkylated Tacrine Derivatives as Potential Agents in Alzheimer's Disease Therapy
- Author
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Jan Korabecny, Ngoc Lam Pham, Rafael Dolezal, Martin Vališ, Kamil Kuca, Ondrej Soukup, Jana Janockova, Daniel Jun, Thuy Duong Nguyen, Eugenie Nepovimova, Vendula Hepnarova, Petr Jost, and Lubica Muckova
- Subjects
business.industry ,Hep G2 Cells ,Pharmacology ,medicine.disease ,Acetylcholinesterase ,chemistry.chemical_compound ,Disease therapy ,Neurology ,chemistry ,Curative treatment ,In vivo ,Alzheimer Disease ,Tacrine ,Drug Discovery ,medicine ,Dementia ,Prevalence studies ,Humans ,Neurology (clinical) ,Cholinesterase Inhibitors ,business ,Butyrylcholinesterase ,medicine.drug - 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.
- Published
- 2018
35. Simultaneous determination of malondialdehyde and 3-nitrotyrosine in cultured human hepatoma cells by liquid chromatography-mass spectrometry
- Author
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Nela Vanova, Lubica Muckova, David Herman, Alzbeta Dlabkova, Jaroslav Pejchal, Monika Schmidt, and Daniel Jun
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Oxidative phosphorylation ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Liquid chromatography–mass spectrometry ,Limit of Detection ,Tandem Mass Spectrometry ,Malondialdehyde ,Drug Discovery ,medicine ,Humans ,Derivatization ,Molecular Biology ,Pharmacology ,chemistry.chemical_classification ,Chromatography ,010401 analytical chemistry ,Liver Neoplasms ,Reproducibility of Results ,General Medicine ,Hep G2 Cells ,0104 chemical sciences ,Oxidative Stress ,030104 developmental biology ,chemistry ,Toxicity ,Thiol ,Tyrosine ,Oxidative stress ,Homogenization (biology) ,Chromatography, Liquid - Abstract
Although reactive oxygen/nitrogen species (ROS/RNS) have a fundamental role in physiological processes, enhanced ROS/RNS production induced by exogenous sources, including drugs and other xenobiotics, may result in serious damage to biomolecules. Oxidative/nitrosative stress is being intensively investigated and might be responsible for a variety of health side effects. The present liquid chromatography-tandem mass spectrometry (LC-MS/MS) method provides reliable and accurate simultaneous measurement of malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) in cultured human hepatoma (HepG2) cells. Sample preparation process involving ultrasonic homogenization, alkaline hydrolysis of protein-bound MDA and 3-NT, deproteination, derivatization of MDA by 2,4-dinitrophenylhydrazine and solid-phase extraction was optimized, ensuring the isolation and purification of desired analytes. Additionally, nonprotein thiols and nonprotein disulfides were measured using HPLC-UV. The established lower limit of quantification (0.025 nmol/mL for MDA; 0.0125 nmol/mL for 3-NT) allowed their LC-MS/MS determination in HepG2 cells exposed to model oxidizing agent, tert-butyl hydroperoxide (t-BOOH). The results show significant changes in MDA and 3-NT concentrations and alterations in thiol redox-state in dependence on the t-BOOH concentration and duration of its incubation in HepG2 cells. Concurrent evaluation of oxidative/nitrosative stress biomarkers in the in vitro model may significantly facilitate assessment of toxicity of newly developed drugs in preclinical trials and thus improve their safety profile.
- Published
- 2018
36. Design, Synthesis and in vitro Evaluation of Indolotacrine Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease
- Author
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Kamil Musilek, José Marco-Contelles, Kamil Kuca, Vendula Sepsova, Ondrej Benek, Dominykas Zala, Lukas Hroch, Daniel Jun, Petr Jost, Martina Hrabinova, Rona R. Ramsay, Ondrej Soukup, Marketa Pasdiorova, European Commission, University of St Andrews. School of Biology, and University of St Andrews. Biomedical Sciences Research Complex
- Subjects
0301 basic medicine ,Czech ,Indoles ,Chemistry(all) ,Multi-target-directed ligands ,Cytotoxicity ,QH301 Biology ,Pharmacology ,Ligands ,01 natural sciences ,Biochemistry ,Drug Discovery ,Cost action ,General Pharmacology, Toxicology and Pharmaceutics ,MTDLs ,Hep G2 Cells ,Alzheimer's disease ,Blood-Brain Barrier ,Acetylcholinesterase ,Quinolines ,Tacrine ,language ,Molecular Medicine ,Christian ministry ,Monoamine Oxidase Inhibitors ,Cell Survival ,Library science ,R Medicine ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,QH301 ,03 medical and health sciences ,Alzheimer Disease ,Humans ,Inhibitory concentration 50 ,Monoamine Oxidase ,Cell survival ,Inhibitors ,010405 organic chemistry ,Monoamine oxidase ,Organic Chemistry ,Cholinesterase ,language.human_language ,0104 chemical sciences ,030104 developmental biology ,Design synthesis ,Drug Design ,Cholinesterase Inhibitors - Abstract
This publication was supported by the project Czech National Institute of Mental Health (NIMH – CZ; no. ED2.1.00/03.0078), Ministry of Education, Youth and Sports of the Czech Republic (no. LD14009), MH CZ - DRO (UHHK, 00179906), the University of Defence of the Czech Republic (long term development plan), MINECO (Government of Spain; Grant SAF2012-33304), the School of Biology at the University of St Andrews, and by COST Action CM1103. In this study, novel indolotacrine analogues have been designed, synthesized and evaluated as potential drugs for the treatment of Alzheimer’s disease. Based on a multi-target-directed ligand approach, novel compounds have been designed to act simultaneously as cholinesterase and monoamine oxidase (MAO) inhibitors. Prepared compounds were also evaluated for their antioxidant, cytotoxic, hepatotoxic and permeability (Blood-Brain Barrier penetration) properties. Indolotacrine 9b (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 being a potent inhibitor of acetylcholinesterase (IC50 = 1.5 µM), butyrylcholinesterase (IC50 = 2.4 µM) and monoamine oxidase A (IC50 = 0.49 µM) and a weak inhibitor of monoamine oxidase B (IC50 = 53.9 µM). Although its cytotoxic (IC50 = 5.5 ± 0.4 µM) and hepatotoxic (IC50 = 1.22 ± 0.11 µM) profile is not as good as the standard 7-methoxytacrine (IC50 = 63 ± 4 µM and IC50 = 11.50 ± 0.77 µM respectively), the overall improvement in the inhibitory activities and potential to cross blood-brain barrier make indolotacrine 9b a promising lead compound for further development and investigation. Postprint
- Published
- 2015
37. Isoquinoline alkaloids as prolyl oligopeptidase inhibitors
- Author
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Marcela Šafratová, Lucie Hulová, Lubomír Opletal, Lucie Cahlíková, Anna Hošťálková, Martina Hrabinova, Miroslav Ločárek, Kateřina Macáková, Daniel Jun, Jakub Chlebek, and Markéta Adamcová
- Subjects
Pharmacology ,Aporphines ,Serine Proteinase Inhibitors ,Molecular Structure ,Serine Endopeptidases ,Oligopeptidase ,Dioxoles ,General Medicine ,Isoquinolines ,Heterocyclic Compounds, 4 or More Rings ,chemistry.chemical_compound ,Cytosol ,Alkaloids ,Biochemistry ,chemistry ,Californidine ,Drug Discovery ,Corypalmine ,Serine peptidase ,Proline ,Isoquinoline ,Prolyl Oligopeptidases ,IC50 - Abstract
Prolyl oligopeptidase is a cytosolic serine peptidase that hydrolyses proline-containing peptides at the carboxy terminus of proline residues. It has been associated with schizophrenia, bipolar affective disorder, and related neuropsychiatric disorders and therefore may have important clinical implications. Thirty-one isoquinoline alkaloids of various structural types, previously isolated in our laboratory, were screened for their ability to inhibit prolyl oligopeptidase. Promising results have been showed by alkaloids californidine (IC50=55.6±3.5 μM), dihydrosanquinarine (IC50=99.1±7.6 μM), corypalmine (IC50=128.0±10.5 μM) and N-methyllaurotetanine (IC50=135.0±11.7 μM).
- Published
- 2015
38. Design, synthesis and in vitro testing of 7-methoxytacrine-amantadine analogues: a novel cholinesterase inhibitors for the treatment of Alzheimer’s disease
- Author
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Katarina Siposova, Kamil Musilek, Daniel Jun, Zuzana Gazova, Anna Horova, Eugenie Nepovimova, Katarina Spilovska, Jan Korabecny, Rafael Dolezal, Kamil Kuca, and Lucie Drtinova
- Subjects
biology ,Stereochemistry ,Organic Chemistry ,Amantadine ,Pharmacology ,Acetylcholinesterase ,In vitro ,chemistry.chemical_compound ,chemistry ,Thiourea ,biology.protein ,Urea ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Binding site ,Butyrylcholinesterase ,Cholinesterase ,medicine.drug - Abstract
A series of cholinesterase inhibitors acting as dual binding site heterodimers for the management of Alzheimer’s disease were developed. The series of 7-methoxytacrine (7-MEOTA)-amantadine ureas (11–17) was designed, prepared evaluated in vitro towards human acetyl/butyryl cholinesterase (hAChE, hBChE) and compared with the series of 7-MEOTA-amantadine thioureas (4–10). The heterodimers have different length of linkers combining 7-MEOTA and amantadine moieties. In comparison with 7-MEOTA, the newly synthesized compounds were better inhibitors of both cholinesterases. The urea analogues did not have the anticipated benefit of increased inhibitory activity and have comparable IC50 values with thiourea derivatives.
- Published
- 2015
39. Cholinergic properties of new 7-methoxytacrine-donepezil derivatives
- Author
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Vendula Sepsova, Jana Z. Karasova, Gunnar Tobin, Daniel Jun, Jan Korabecny, Pavla Cabelova, Katerina Janska, Jan Krusek, Kristyna Skrenkova, Kamil Kuca, Marian Valko, and Ondrej Soukup
- Subjects
Male ,Synaptic cleft ,Physiology ,Muscle Fibers, Skeletal ,Biophysics ,Muscarinic Antagonists ,Nicotinic Antagonists ,Pharmacology ,Cholinergic Antagonists ,chemistry.chemical_compound ,Piperidines ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Donepezil ,Patch clamp ,Rats, Wistar ,Cells, Cultured ,Dose-Response Relationship, Drug ,General Medicine ,Acetylcholinesterase ,Rats ,Nicotinic agonist ,chemistry ,Mechanism of action ,Indans ,Tacrine ,Cholinergic ,medicine.symptom ,Acetylcholine ,medicine.drug - 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.
- Published
- 2015
40. Prolyl oligopeptidase and its role in the organism: attention to the most promising and clinically relevant inhibitors
- Author
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Eugenie Nepovimova, Katerina Babkova, Jan Korabecny, Ondrej Soukup, Kamil Kuca, and Daniel Jun
- Subjects
0301 basic medicine ,Models, Molecular ,Research groups ,Serine Proteinase Inhibitors ,Oligopeptidase ,Biology ,Pharmacology ,03 medical and health sciences ,Structure-Activity Relationship ,Prolyl endopeptidase ,Drug Discovery ,medicine ,Animals ,Humans ,Cognitive impairment ,Organism ,chemistry.chemical_classification ,Molecular Structure ,Serine Endopeptidases ,030104 developmental biology ,Enzyme ,chemistry ,Molecular Medicine ,Signal transduction ,Prolyl Oligopeptidases ,Hormone ,medicine.drug - Abstract
Prolyl oligopeptidase (POP), also called prolyl endopeptidase, is a cytosolic enzyme investigated by several research groups. It has been proposed to play an important role in physiological processes such as modulation of the levels of several neuronal peptides and hormones containing a proline residue. Due to its proteolytic activity and physiological role in cell signaling pathways, inhibition of POP offers an emerging approach for the treatment of Alzheimer's and Parkinson's diseases as well as other diseases related to cognitive impairment. Furthermore, it may also represent an interesting target for treatment of neuropsychiatric disorders, and as an antiangiogenesis or antineoplastic agent. In this review paper, we summarized naturally occurring POP inhibitors together with peptide-like inhibitors and their biological effects. Some of them have shown promising results and interesting pharmacological profiles. However, to date, there is no POP inhibitor available on the market although several clinical trials have been undertaken.
- Published
- 2017
41. Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006-2016)
- Author
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Ondrej Soukup, Rafael Dolezal, Lukas Gorecki, Eugenie Nepovimova, Kamil Kuca, Tomas Kucera, Daniel Jun, David Malinak, Kamil Musilek, and Jan Korabecny
- Subjects
0301 basic medicine ,Chemical Warfare Agents ,Cholinesterase Reactivators ,Antidotes ,Cholinergic crisis ,Pharmacology ,Organophosphate poisoning ,Patents as Topic ,03 medical and health sciences ,chemistry.chemical_compound ,Organophosphate Poisoning ,Organophosphorus Compounds ,Drug Discovery ,medicine ,Animals ,Humans ,Cholinesterase ,Nerve agent ,biology ,Organophosphate ,General Medicine ,medicine.disease ,Acetylcholinesterase ,030104 developmental biology ,chemistry ,Drug Design ,biology.protein ,Cholinesterase Inhibitors ,medicine.drug - Abstract
organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function. Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication. Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes.
- Published
- 2017
42. Some Possibilities to Study New Prophylactics against Nerve Agents
- Author
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Tomas Kucera, Daniel Jun, Jiri Bajgar, Jiri Kassa, Kamil Musilek, and Kamil Kuca
- Subjects
Models, Molecular ,Chemical Warfare Agents ,Cholinesterase Reactivators ,Transdermal patch ,medicine.medical_treatment ,Poison control ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Detoxification ,Drug Discovery ,medicine ,Animals ,Cholinesterases ,Humans ,Antidote ,030304 developmental biology ,Nerve agent ,Benactyzine ,0303 health sciences ,business.industry ,General Medicine ,Pyridostigmine ,business ,Nerve Agents ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Nerve agents belong to the most dangerous chemical warfare agents and can be/were misused by terrorists. Effective prophylaxis and treatment is necessary to diminish their effect. General principles of prophylaxis are summarized (protection against acetylcholinesterase inhibition, detoxification, treatment “in advance” and use of different drugs). They are based on the knowledge of mechanism of action of nerve agents. Among different examinations, it is necessary to test prophylactic effectivity in vivo and compare the results with protection in vitro. Chemical and biological approaches to the development of new prophylactics would be applied simultaneously during this research. Though the number of possible prophylactics is relatively high, the only four drugs were introduced into military medical practice. At present, pyridostigmine seems to be common prophylactic antidote; prophylactics panpal (tablets with pyridostigmine, trihexyphenidyl and benactyzine), transant (transdermal patch containing HI-6) are other means introduced into different armies as prophylactics. Scavenger commercionally available is Protexia®. Future development will be focused on scavengers, and on other drugs either reversible cholinesterase inhibitors (e.g., huperzine A, gallantamine, physostigmine, acridine derivatives) or other compounds.
- Published
- 2017
43. Activity of cholinesterases in a young and healthy middle-European population: Relevance for toxicology, pharmacology and clinical praxis
- Author
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Daniel Jun, Jan Misik, Vit Rehacek, Zuzana Maderycova, Jana Zdarova Karasova, Martina Tumova, and Kamil Kuca
- Subjects
0301 basic medicine ,Male ,Pharmacology ,Toxicology ,chemistry.chemical_compound ,Hemoglobins ,0302 clinical medicine ,Organophosphate Poisoning ,Reference Values ,Mass Casualty Incidents ,Butyrylcholinesterase ,Nerve agent ,Czech Republic ,biology ,Chemistry ,Smoking ,Age Factors ,General Medicine ,Middle Aged ,Acetylcholinesterase ,Healthy Volunteers ,language ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Aché ,GPI-Linked Proteins ,Organophosphate poisoning ,Occupational medicine ,03 medical and health sciences ,Young Adult ,Sex Factors ,Internal medicine ,medicine ,Humans ,Occupational Health ,Cholinesterase ,medicine.disease ,language.human_language ,030104 developmental biology ,Endocrinology ,biology.protein ,Hemoglobin ,030217 neurology & neurosurgery ,Biomarkers - Abstract
The activity of human cholinesterases, erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7) and plasma butyrylcholinesterase (BChE; EC 3.1.1.8) represents an important marker when monitoring exposure to pesticides/nerve agents, and may also be used in occupational medicine in diagnosis and prognosis of some diseases. In this study "normal/baseline" AChE and BChE activity has been investigated in a young and healthy population, with subsequent evaluation of several intra-population factors including sex, age (categories 18-25, 26-35 and 36-45 years old) and smoker status. The modified Ellman's method was used for enzyme activity assessment in 387 young and healthy individuals (201 males and 186 females aged 18-45). A significant inter-sexual difference in AChE and BChE activity was found (AChE: 351±67 for males and 377±65 for females, (μmol/min)/(μmol of hemoglobin), p0.001; BChE: 140±33 for males and 109±29 for females, μkat/l, p0.001; mean±SD). Despite the finding that mean AChE activity somewhat decreased whereas BChE activity grew within the age categories of the tested subjects, no significant effect of age on cholinesterase activity was found (p0.05). Smoking influenced cholinesterase activity - AChE activity in smokers was elevated (approx. 3% in males; 8% in females) relative to that in non-smokers (p0.05). Smoking was found not to have any effect on BChE activity. Reference values based on confidence intervals for AChE and BChE activity were established. The presented results might be useful in routine clinical practice where the monitoring of blood AChE and plasma BChE activity is crucial for prognosis and diagnosis of organophosphate poisoning, in occupational medicine and in relevant mass casualty scenarios.
- Published
- 2017
44. Evaluation of the antioxidant activity of several naturally occurring coumarins and their synthesized analogues by 'ferric reducing antioxidant power' assay
- Author
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Daniel Jun, Vit Koleckar, Lubomír Opletal, Zuzana Rehakova, Kamil Kuca, Ludek Jahodar, Lucie Cahlíková, and Katerina Macáková
- Subjects
Pharmacology ,Antioxidant ,Chemistry ,medicine.medical_treatment ,Oxidation reduction ,General Medicine ,Ferric Compounds ,Antioxidants ,Reducing capacity ,Coumarins ,Biological property ,Drug Discovery ,medicine ,Ferric ,Structure–activity relationship ,Organic chemistry ,heterocyclic compounds ,Oxidation-Reduction ,medicine.drug - Abstract
Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. According to our continuing investigations of biological effects of several coumarins, the structure-antioxidant activity relationships (SARs) of six naturally occurring coumarins and their 16 synthesized analogues were established. For this purpose, the very reliable colorimetric assay (ferric reducing antioxidant power) modified to be used in 96-well microplates was used. This approach, which determines the reducing capacity of tested compounds directly, has previously been used for the determination of SARs of flavonoids, but has not been used for SAR determination of coumarins. It is known that the biological properties and consequently, therapeutic application of simple coumarins depends upon the pattern of substitution. It was established that 7,8-dihydroxy- and 6,7-dihydroxy-4-methylcoumarins have shown excellent ferric-reducing properties.
- Published
- 2013
45. The interaction of standard oxime reactivators with hemicholinium-3 sensitive choline carriers
- Author
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Daniel Jun, Kamil Kuca, Ondrej Soukup, Vojtech Tambor, Zdena Kristofikova, and Daniela Ripova
- Subjects
Male ,Obidoxime ,Cholinesterase Reactivators ,Pralidoxime ,Membrane Fluidity ,Pharmacology ,Tritium ,Toxicology ,Hippocampus ,Choline ,chemistry.chemical_compound ,Hemicholinium-3 ,medicine ,Membrane fluidity ,Animals ,Trimedoxime ,Rats, Wistar ,Cell Membrane ,Membrane Transport Proteins ,Hemicholinium 3 ,General Medicine ,Acetylcholinesterase ,Rats ,chemistry ,Biochemistry ,Anisotropy ,Cholinergic ,Acetylcholine ,Synaptosomes ,medicine.drug - Abstract
Organophosphorus poisoning manifests as a cholinergic syndrome due to an inhibition of acetylcholinesterase. It is treated symptomatically by anticholinergics and oxime reactivators are used as causal antidotes. Reactivators possess a complex mechanism of action and interact at various levels of the cholinergic transmission. The aim of this study was to investigate the effect of standard oxime reactivators (HI-6, obidoxime, trimedoxime, methoxime and pralidoxime) on the hemicholinium-3 sensitive carriers, which are involved in the high-affinity choline uptake (HACU) transport, a key regulatory step in the synthesis of acetylcholine. The activity of the carriers was estimated in vitro on hippocampal synaptosomes using the substrate (3H)-choline and the competitive inhibitor (3H)-hemicholinium-3. Furthermore, the effect of the reactivators on the fluidity of hippocampal membranes was assessed. All tested compounds, except methoxime, showed an acute inhibitory effect on the carriers, however, only at μM concentrations. Trimedoxime showed the highest potency to inhibit HACU among all tested compounds ( I max 62%, IC 50 = 3 μM). All compounds, except HI-6, influenced also a membrane fluidity in the region of the hydrophilic heads of phospholipid bilayer, nevertheless, only methoxime was able to penetrate more deeply into the hydrocarbon core. We suggest that the direct interaction of oxime reactivators with the carrier protein (HI-6 and trimedoxime) and/or the changes in carrier conformation mediated by alterations in membrane fluidity (trimedoxime, obidoxime and pralidoxime) could occur here. The influence of reactivators on the carriers could be unfavorable in the case of their prolonged administration in vivo. From this point of view, the application of methoxime appears to be the best.
- Published
- 2012
46. 7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment
- Author
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Rafael Dolezal, Martin Andrs, David Malinak, Eva Mezeiova, Jan Korabecny, Lukas Gorecki, Daniel Jun, Anna Horova, Eugenie Nepovimova, Ondrej Soukup, Martina Hrabinova, Katerina Babkova, Vendula Sepsova, and Kamil Kuca
- Subjects
Pharmaceutical Science ,tacrine ,Pharmacology ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,Structure-Activity Relationship ,7-methoxy-tacrine ,lcsh:Organic chemistry ,Drug Discovery ,medicine ,Structure–activity relationship ,Humans ,Physical and Theoretical Chemistry ,Binding site ,Butyrylcholinesterase ,Cholinesterase ,Alzheimer’s disease ,acetylcholinesterase ,butyrylcholinesterase ,MTDLs ,Amyloid beta-Peptides ,Aniline Compounds ,Binding Sites ,biology ,Organic Chemistry ,Memantine ,Acetylcholinesterase ,Recombinant Proteins ,Molecular Docking Simulation ,Kinetics ,chemistry ,Chemistry (miscellaneous) ,Docking (molecular) ,Tacrine ,biology.protein ,Molecular Medicine ,Cholinesterase Inhibitors ,medicine.drug ,Central Nervous System Agents - 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.
- Published
- 2015
47. Tacrine - tryptophan derivatives – novel agents against the Alzheimer’s disease
- Author
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J. Karasova-Zdarova, Daniel Jun, Kamil Kuca, K. Vales, E. Nepovimova, Jan Korabecny, Ondřej Soukup, and J. Ricny
- Subjects
Neurology ,Chemistry ,Novel agents ,Tacrine ,medicine ,Tryptophan ,Neurology (clinical) ,Pharmacology ,medicine.drug - Published
- 2017
48. ON THE UNIVERSALITY OF OXIME HLö-7 - ANTIDOTE FOR CASE OF THE NERVE AGENT POISONING
- Author
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Miroslav Pohanka, Kamil Musilek, Kallol K. Ghosh, Ondrej Soukup, Martina Hrabinova, Hradec Kralove, Daniel Jun, Kamil Kuca, and Jana Žd'árová Karasová
- Subjects
Emergency Medical Services ,Sarin ,Stereochemistry ,Veterinary (miscellaneous) ,medicine.medical_treatment ,Public Health, Environmental and Occupational Health ,Cyclosarin ,Pharmacology ,Oxime ,Acetylcholinesterase ,chemistry.chemical_compound ,Immunology and Microbiology (miscellaneous) ,chemistry ,Soman ,Emergency Medicine ,medicine ,Antidote ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Nerve agent ,medicine.drug ,Tabun - Abstract
Summary Searching for the universal oxime, which could be able to reactivate acetylcholinesterase inhibited by various nerve agents is still topic of high interest. In this contribution, oxime HLo-7, that was thoroughly discussed in the last decade, is evaluated . Its universality was tested in vitro using the rat brain homogenate as a source of the cholinesterases. The main members of the nerve agent family (tabun, sarin, soman, cyclosarin and VX) were used for this purpose. As shown, oxime HLo-7 was able to reactivate cholinesterases inhibited by all tested nerve agents with the exception of tabun. Hence, it could not be designated as the broad-spectrum reactivator.
- Published
- 2011
49. 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
- Author
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Florian Nachon, Jana Hroudová, Ondrej Holas, Kamil Musilek, Daniel Jun, Zdenek Fisar, Filip Zemek, Jan Korabecny, Vlastimil Dohnal, Veronika Opletalova, Jiri Patocka, Eugenie Nepovimova, and Kamil Kuca
- Subjects
Drug Evaluation, Preclinical ,tacrine ,Pharmaceutical Science ,Pharmacology ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Alzheimer Disease ,7-MEOTA ,Drug Discovery ,medicine ,Cholinesterases ,Humans ,Physical and Theoretical Chemistry ,Butyrylcholinesterase ,Cholinesterase ,chemistry.chemical_classification ,biology ,Communication ,Organic Chemistry ,acetylcholinesterase ,medicine.disease ,Acetylcholinesterase ,inhibition ,In vitro ,Enzyme ,chemistry ,Chemistry (miscellaneous) ,Tacrine ,biology.protein ,Acridines ,Molecular Medicine ,Amine gas treating ,Cholinesterase Inhibitors ,Alzheimer's disease ,Heterocyclic Compounds, 3-Ring ,medicine.drug - 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.
- Published
- 2010
50. The effect of trimedoxime on acetylcholinesterase and on the cholinergic system of the rat bladder
- Author
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Ondřej Holas, Jiří Binder, Josef Fusek, Kamil Kuca, Daniel Jun, Ondřej Soukup, Kumar Killy, and Gunnar Tobin
- Subjects
Obidoxime ,General Immunology and Microbiology ,Paraoxon ,Aché ,General Neuroscience ,Health, Toxicology and Mutagenesis ,Biomedical Engineering ,General Medicine ,Pharmacology ,Acetylcholinesterase ,Muscarinic agonist ,General Biochemistry, Genetics and Molecular Biology ,language.human_language ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Artificial Intelligence ,Muscarinic acetylcholine receptor ,language ,medicine ,Trimedoxime ,General Pharmacology, Toxicology and Pharmaceutics ,General Agricultural and Biological Sciences ,Tabun ,medicine.drug - Abstract
Summary Trimedoxime is a bisquaternary oxime that is widely used in the treatment of organophosphorous poisoning caused by tabun and paraoxon. We tested its affinity to acetylcholinesterase (AChE), its mechanism of interaction and effect on the cholinergic system of the rat bladder. The half maximal inhibitory concentration (IC 50 ) of trimedoxime to recombinant AChE was found to be 82.0 mM ± 30.1 mM. This represents a weak inhibition. Its interaction with AChE seems to be very similar to obidoxime – one aromatic nucleus interacts with the peripheral anionic site and the other with the residues TYR337 and TYR341 inside the cavity. Also the oxime moiety is moving towards the catalytic triade ready for the reactivation of the inhibited AChE. In the organ bath experiment no significant effect of trimedoxime was observed on the contraction of the detrusor caused by the muscarinic agonist metacholine.
- Published
- 2010
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