Brominated oxime nucleophiles are efficiently reactivating cholinesterases inhibited by nerve agents
Jazyk angličtina Země Německo Médium print-electronic
Typ dokumentu časopisecké články
Grantová podpora
GA21-03000S
Grantová Agentura České Republiky
SV2112-2023
Univerzita Hradec Králové
PubMed
38789714
DOI
10.1007/s00204-024-03791-6
PII: 10.1007/s00204-024-03791-6
Knihovny.cz E-zdroje
- Klíčová slova
- Cholinesterase, Nerve agent, Nucleophile, Organophosphate, Oxime, Reactivation,
- MeSH
- acetylcholinesterasa * metabolismus účinky léků MeSH
- butyrylcholinesterasa * metabolismus MeSH
- chemické bojové látky toxicita MeSH
- cholinesterasové inhibitory * toxicita farmakologie MeSH
- halogenace MeSH
- krysa rodu Rattus MeSH
- nervová bojová látka * toxicita MeSH
- organothiofosforové sloučeniny * toxicita MeSH
- oximy * farmakologie chemie MeSH
- potkani Wistar MeSH
- pyridinové sloučeniny farmakologie MeSH
- reaktivátory cholinesterasy * farmakologie chemie MeSH
- sarin * toxicita MeSH
- stabilita léku MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- acetylcholinesterasa * MeSH
- butyrylcholinesterasa * MeSH
- chemické bojové látky MeSH
- cholinesterasové inhibitory * MeSH
- nervová bojová látka * MeSH
- organothiofosforové sloučeniny * MeSH
- oximy * MeSH
- pyridinové sloučeniny MeSH
- reaktivátory cholinesterasy * MeSH
- sarin * MeSH
- VX MeSH Prohlížeč
Six novel brominated bis-pyridinium oximes were designed and synthesized to increase their nucleophilicity and reactivation ability of phosphorylated acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Their pKa was valuably found lower to parent non-halogenated oximes. Stability tests showed that novel brominated oximes were stable in water, but the stability of di-brominated oximes was decreased in buffer solution and their degradation products were prepared and characterized. The reactivation screening of brominated oximes was tested on AChE and BChE inhibited by organophosphorus surrogates. Two mono-brominated oximes reactivated AChE comparably to non-halogenated analogues, which was further confirmed by reactivation kinetics. The acute toxicity of two selected brominated oximes was similar to commercially available oxime reactivators and the most promising brominated oxime was tested in vivo on sarin- and VX-poisoned rats. This brominated oxime showed interesting CNS distribution and significant reactivation effectiveness in blood. The same oxime resulted with the best protective index for VX-poisoned rats.
Zobrazit více v PubMed
Arnett EM, Reich R (1980) Electronic effects on the Menshutkin reaction. A complete kinetic and thermodynamic dissection of alkyl transfer to 3- and 4-substituted pyridines. J Am Chem Soc 102:5892–5902. https://doi.org/10.1021/ja00538a031 DOI
Bajgar J (2004) Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. In: Advances in Clinical Chemistry. Elsevier, pp 151–216
Čadež T, Kolić D, Šinko G, Kovarik Z (2021) Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase. Sci Rep 11:21486. https://doi.org/10.1038/s41598-021-00953-9 PubMed DOI PMC
Carletti E, Colletier J-P, Dupeux F et al (2010) Structural evidence that human acetylcholinesterase inhibited by tabun ages through o-dealkylation. J Med Chem 53:4002–4008. https://doi.org/10.1021/jm901853b PubMed DOI
Clayden J, Greeves N, Warren S (2012) Organic chemistry, 2nd edn. OUP Oxford DOI
Eichler T, Hauptmann S (2003) The chemistry of heterocycles: structures, reactions, synthesis, and applications, Wiley-VCH Verag GmbH&Co. KGaA
Ellman GL, Courtney KD, Andres V, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95. https://doi.org/10.1016/0006-2952(61)90145-9 PubMed DOI
Franjesevic AJ, Sillart SB, Beck JM et al (2019) Resurrection and reactivation of acetylcholinesterase and butyrylcholinesterase. Chem Eur J 25:5337–5371. https://doi.org/10.1002/chem.201805075 PubMed DOI
Gorecki L, Andrys R, Schmidt M et al (2020) Cysteine-targeted insecticides against A. gambiae acetylcholinesterase are neither selective nor reversible inhibitors. ACS Med Chem Lett 11:65–71. https://doi.org/10.1021/acsmedchemlett.9b00477 PubMed DOI
Gupta R (2015) Handbook of toxicology of chemical warfare agents, 2nd edn. Academic Press Elsevier, Amsterdam
Gupta B, Sharma R, Singh N et al (2013) In vitro reactivation kinetics of paraoxon- and DFP-inhibited electric eel AChE using mono- and bis-pyridinium oximes. Arch Toxicol https://doi.org/10.1007/s00204-013-1136-z PubMed DOI
Howes L (2020) Novichok compound poisoned Navalny. C&EN Global Enterp 98:5–5. https://doi.org/10.1021/cen-09835-scicon3 DOI
John H, van der Schans MJ, Koller M et al (2018) Fatal sarin poisoning in Syria 2013: forensic verification within an international laboratory network. Forensic Toxicol 36:61–71. https://doi.org/10.1007/s11419-017-0376-7 PubMed DOI
Karasova JZ, Zemek F, Bajgar J et al (2011) Partition of bispyridinium oximes (trimedoxime and K074) administered in therapeutic doses into different parts of the rat brain. J Pharm Biomed Anal 54:1082–1087. https://doi.org/10.1016/j.jpba.2010.11.024 PubMed DOI
Karasova J, Zemek F, Musilek K, Kuca K (2012) Time-dependent changes of oxime K027 concentrations in different parts of rat central nervous system. Neurotox Res https://doi.org/10.1007/s12640-012-9329-4 PubMed DOI
Karasova JZ, Kvetina J, Tacheci I et al (2017a) Pharmacokinetic profile of promising acetylcholinesterase reactivators K027 and K203 in experimental pigs. Toxicol Lett 273:20–25. https://doi.org/10.1016/j.toxlet.2017.03.017 PubMed DOI
Karasova JZ, Maderycova Z, Tumova M et al (2017b) Activity of cholinesterases in a young and healthy middle-European population: relevance for toxicology, pharmacology and clinical praxis. Toxicol Lett 277:24–31. https://doi.org/10.1016/j.toxlet.2017.04.017 PubMed DOI
Katalinić M, Maček Hrvat N, Žďárová Karasová J et al (2015) Translation of in vitro to in vivo pyridinium oxime potential in tabun poisoning. Arh Hig Rada Toksikol 66:291–298. https://doi.org/10.1515/aiht-2015-66-2740 PubMed DOI
Kohoutova Z, Malinak D, Andrys R et al (2022) Charged pyridinium oximes with thiocarboxamide moiety are equally or less effective reactivators of organophosphate-inhibited cholinesterases compared to analogous carboxamides. J Enzyme Inhib Med Chem 37:760–767. https://doi.org/10.1080/14756366.2022.2041628 PubMed DOI PMC
Kuca K, Bielavský J, Cabal J, Bielavská M (2003a) Synthesis of a potential reactivator of acetylcholinesterase—1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane bromide. Tetrahedron Lett 44:3123–3125. https://doi.org/10.1016/S0040-4039(03)00538-0 DOI
Kuča K, Bielavský J, Cabal J, Kassa J (2003b) Synthesis of a new reactivator of tabun-inhibited acetylcholinesterase. Bioorg Med Chem Lett 13:3545–3547. https://doi.org/10.1016/S0960-894X(03)00751-0 PubMed DOI
Kuca K, Jun D, Bajgar J (2007) Currently used cholinesterase reactivators against nerve agent intoxication: comparison of their effectivity in vitro. Drug Chem Toxicol 30:31–40. https://doi.org/10.1080/01480540601017637 PubMed DOI
Lei C, Sun X (2018) Comparing lethal dose ratios using probit regression with arbitrary slopes. BMC Pharmacol Toxicol 19:61. https://doi.org/10.1186/s40360-018-0250-1 PubMed DOI PMC
Meek E, Chambers H, Coban A et al (2012) Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates. Toxicol Sci 126:525–533. https://doi.org/10.1093/toxsci/kfs013 PubMed DOI
Millard CB, Kryger G, Ordentlich A et al (1999) Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level. Biochemistry 38:7032–7039. https://doi.org/10.1021/bi982678l PubMed DOI
Misik J, Pavlikova R, Cabal J, Kuca K (2015) Acute toxicity of some nerve agents and pesticides in rats. Drug Chem Toxicol 38:32–36. https://doi.org/10.3109/01480545.2014.900070 PubMed DOI
Misik J, Nepovimova E, Pejchal J et al (2018) Cholinesterase inhibitor 6-chlorotacrine—in vivo toxicological profile and behavioural effects. Curr Alzheimer Res 15:552–560. https://doi.org/10.3109/01480545.2014.900070 PubMed DOI
Moshiri M, Darchini-Maragheh E, Balali-Mood M (2012) Advances in toxicology and medical treatment of chemical warfare nerve agents. Daru J Pharm Sci 20:81. https://doi.org/10.1186/2008-2231-20-81 DOI
Musil K, Florianova V, Bucek P et al (2016) Development and validation of a FIA/UV–vis method for pKa determination of oxime based acetylcholinesterase reactivators. J Pharm Biomed Anal 117:240–246. https://doi.org/10.1016/j.jpba.2015.09.010 PubMed DOI
Musilek K, Jun D, Cabal J et al (2007) Design of a potent reactivator of tabun-inhibited acetylcholinesterase–synthesis and evaluation of (E)-1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide (K203). J Med Chem 50:5514–5518. https://doi.org/10.1021/jm070653r PubMed DOI
Musilek K, Malinak D, Nepovimova E et al (2020) Chapter 69—novel cholinesterase reactivators. In: Gupta RC (ed) Handbook of toxicology of chemical warfare agents, 3rd edn. Academic Press, Boston, pp 1161–1177 DOI
Nepovimova E, Kuca K (2018) Chemical warfare agent NOVICHOK—mini-review of available data. Food Chem Toxicol 121:343–350. https://doi.org/10.1016/j.fct.2018.09.015 PubMed DOI
Pejchal J, Novotný J, Mařák V et al (2012) Activation of p38 MAPK and expression of TGF-β1 in rat colon enterocytes after whole body γ-irradiation. Int J Radiat Biol 88:348–358. https://doi.org/10.3109/09553002.2012.654044 PubMed DOI
Quinn DM (1987) Acetylcholinesterase: enzyme structure, reaction dynamics, and virtual transition states. Chem Rev 87:955–979. https://doi.org/10.1021/cr00081a005 DOI
Saint-André G, Kliachyna M, Kodepelly S et al (2011) Design, synthesis and evaluation of new α-nucleophiles for the hydrolysis of organophosphorus nerve agents: application to the reactivation of phosphorylated acetylcholinesterase. Tetrahedron 67:6352–6361. https://doi.org/10.1016/j.tet.2011.05.130 DOI
Sakurada K, Matsubara K, Shimizu K et al (2003) Pralidoxime iodide (2-PAM) penetrates across the blood-brain barrier. Neurochem Res 28:1401–1407. https://doi.org/10.1023/a:1024960819430 PubMed DOI
Smith D, Anderson D, Degryse A-D et al (2018) Classification and reporting of severity experienced by animals used in scientific procedures: FELASA/ECLAM/ESLAV Working Group report. Lab Anim 52:5–57. https://doi.org/10.1177/0023677217744587 PubMed DOI PMC
Tallarida RJ, Murray RB (1986) Manual of pharmacologic calculations. Springer, New York DOI
Tambara K, Pantoş GD (2013) Conversion of aldoximes into nitriles and amides under mild conditions. Org Biomol Chem 11:2466–2472. https://doi.org/10.1039/C3OB27362H PubMed DOI
Tu AT (1999) Overview of sarin terrorist attacks in Japan. In: Natural and selected synthetic toxins. J Am Chem Soc pp 304–317. https://doi.org/10.1021/bk-2000-0745.ch020
Vanova N, Hojna A, Pejchal J et al (2021) Determination of K869, a novel oxime reactivator of acetylcholinesterase, in rat body fluids and tissues by liquid-chromatography methods: pharmacokinetic study. J Pharm Sci 110:1842–1852. https://doi.org/10.1016/j.xphs.2021.01.031 PubMed DOI
Vega JA, Vaquero JJ, Alvarez-Builla J et al (1999) A new approach to the synthesis of 2-aminoimidazo[1,2-a]pyridine derivatives through microwave-assisted N-alkylation of 2-halopyridines. Tetrahedron 55:2317–2326. https://doi.org/10.1016/S0040-4020(99)00012-5 DOI
Watson A, Opresko D, Young RA et al (2015) Chapter 9—organophosphate nerve agents. In: Gupta RC (ed) Handbook of toxicology of chemical warfare agents, 2nd edn. Academic Press, Boston, pp 87–109 DOI
Worek F, Mast U, Kiderlen D et al (1999) Improved determination of acetylcholinesterase activity in human whole blood. Clin Chim Acta 288:73–90. https://doi.org/10.1016/S0009-8981(99)00144-8 PubMed DOI
Worek F, Thiermann H, Szinicz L, Eyer P (2004) Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes. Biochem Pharmacol 68:2237–2248. https://doi.org/10.1016/j.bcp.2004.07.038 PubMed DOI
Worek F, von der Wellen J, Musilek K et al (2012) Reactivation kinetics of a homologous series of bispyridinium bis-oximes with nerve agent-inhibited human acetylcholinesterase. Arch Toxicol 86:1379–1386. https://doi.org/10.1007/s00204-012-0842-2 PubMed DOI
Žďárová Karasová J, Zemek F, Kassa J, Kuča K (2014) Entry of oxime K027 into the different parts of rat brain: comparison with obidoxime and oxime HI-6. J Appl Biomed 12:25–29. https://doi.org/10.1016/j.jab.2013.01.001 DOI
Zdarova Karasova J, Hepnarova V, Andrys R et al (2020a) Encapsulation of oxime K027 into cucurbit[7]uril: in vivo evaluation of safety, absorption, brain distribution and reactivation effectiveness. Toxicol Lett 320:64–72. https://doi.org/10.1016/j.toxlet.2019.11.021 PubMed DOI
Zdarova Karasova J, Mzik M, Kucera T et al (2020b) Interaction of Cucurbit[7]uril with oxime K027, atropine, and paraoxon: risky or advantageous delivery system? Int J Mol Sci 21:7883. https://doi.org/10.3390/ijms21217883 PubMed DOI PMC
Zdarova Karasova J, Soukup O, Korabecny J et al (2021) Tacrine and its 7-methoxy derivate; time-change concentration in plasma and brain tissue and basic toxicological profile in rats. Drug Chem Toxicol 44:207–214. https://doi.org/10.1080/01480545.2019.1566350 PubMed DOI
Zorbaz T, Malinak D, Maraković N et al (2018) Pyridinium oximes with ortho-positioned chlorine moiety exhibit improved physicochemical properties and efficient reactivation of human acetylcholinesterase inhibited by several nerve agents. J Med Chem 61:10753–10766. https://doi.org/10.1021/acs.jmedchem.8b01398 PubMed DOI
Zorbaz T, Malinak D, Hofmanova T et al (2022) Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents. Eur J Med Chem 238:114377. https://doi.org/10.1016/j.ejmech.2022.114377 PubMed DOI