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Experimental hydrophilic reactivator: bisoxime with three positive charges

  • Kamil Kuca
  • Eugenie Nepovimova
  • Qinghua Wu
  • Felipe Rodrigues de Souza
  • Teodorico de Castro Ramalho
  • Tanos Celmar Costa Franca
  • Kamil Musilek
Short Communication

Abstract

Within this study, experimental hydrophilic acetylcholinesterase (AChE) reactivator was evaluated in vitro against selected nerve agents (cyclosarin, tabun, sarin, VX agent). High hydrophilicity of the reactivator is caused by the presence of three positive charges in its molecule. Quaternary moiety involved in the connecting chain can influence linker’s interaction with the inner of the AChE. For the detailed description of reactivator-AChE interaction, docking studies were performed on theoretical models constructed from the chrystallographic structure of Mus musculus AChE (MmAChE).

Keywords

Reactivator Oxime AChE Nerve agent Docking study 

Notes

Acknowledgement

This work was supported by the Czech Science Foundation (no. 18-01734S), University of Hradec Kralove (FIM Excelence) and Ministry of Defence of the Czech Republic (long term development plan).

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.

References

  1. Acharya J, Dubey DK, Srivastava AK, Raza SK (2011) In vitro reactivation of sarin-inhibited human acetylcholinesterase (AChE) by bis-pyridinium oximes connected by xylene linkers. Toxicol In Vitro 25:251–256.  https://doi.org/10.1016/j.tiv.2010.07.024 CrossRefPubMedGoogle Scholar
  2. Almeida JSFD, Cuya Guizado TR, Guimaraes AP, Ramalho TC, Goncalves AS, de Koning MC, Franca TCC (2016) Docking and molecular dynamics studies of peripheral site ligand-oximes as reactivators of sarin-inhibited human acetylcholinesterase. J Biomol Struct Dyn 34:2632–2642.  https://doi.org/10.1080/07391102.2015.1124807 CrossRefPubMedGoogle Scholar
  3. Antonijevic B, Stojiljkovic MP (2007) Unequal efficacy of pyridinium oximes in acute organophosphate poisoning. Clin Med Res 5:71–82.  https://doi.org/10.3121/cmr.2007.701 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bajgar J (2004) Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv Clin Chem 38:151–216.  https://doi.org/10.1016/S0065-2423(04)38006-6 CrossRefPubMedGoogle Scholar
  5. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Bourne PE (2000) The protein data bank. Nucl Acids Res 28:235–242.  https://doi.org/10.1093/nar/28.1.235 CrossRefPubMedGoogle Scholar
  6. Cabal J, Kuca K, Kassa J (2004) Specification of the structure of oximes able to reactivate tabun-inhibited acetylcholinesterase. Bas Clin Pharmacol Toxicol 95:81–86.  https://doi.org/10.1111/j.1742-7843.2004.950207.x CrossRefGoogle Scholar
  7. Calic M, Vrdoljak AL, Radic M, Jelic D, Jun D, Kuca K, Kovarik Z (2006) In vitro and in vivo evaluation of pyridinium oximes: mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity. Toxicology 219:85–96.  https://doi.org/10.1016/j.tox.2005.11.003 CrossRefPubMedGoogle Scholar
  8. de Castro AA, Prandi IG, Kuca K, Ramalho TC (2017) Organophosphorus degrading enzymes: molecular basis and perspectives for enzymatic bioremediation of agrochemicals. Cienc Agrotecnol 41:471–482.  https://doi.org/10.1590/1413-70542017415000417 CrossRefGoogle Scholar
  9. de Koning MC, Joosen MJA, Noort D, van Zuylen A, Tromp MC (2011) Peripheral site ligand-oxime conjugates: a novel concept towards reactivation of nerve agent-inhibited human acetylcholinesterase. Bioorg Med Chem 19:588–594.  https://doi.org/10.1016/j.bmc.2010.10.059 CrossRefPubMedGoogle Scholar
  10. Giacoppo JOS, França TCC, Kuca K, da Cunha EFF, Abagyan R, Mancini DT, Ramalho TC (2015) Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents. J Biomol Struct Dyn 33:2048–2058.  https://doi.org/10.1080/07391102.2014.989408 CrossRefPubMedGoogle Scholar
  11. Gorecki L, Korabecny J, Musilek K, Malinak D, Nepovimova E, Dolezal R, Jun D, Soukup O, Kuca K (2016) SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides. Arch Toxicol 90:2831–2859.  https://doi.org/10.1007/s00204-016-1827-3 CrossRefPubMedGoogle Scholar
  12. Jun D, Stodulka P, Kuca K, Koleckar V, Dolezal B, Simon P, Veverka M (2008) TLC analysis of intermediates arising during the preparation of oxime HI-6 dimethanesulfonate. J Chromatogr Sci 46:316–319.  https://doi.org/10.1093/chromsci/46.4.316 CrossRefPubMedGoogle Scholar
  13. Jun D, Stodulka P, Kuca K, Dolezal B (2010a) High-performance liquid chromatography analysis of by-products and intermediates arising during the synthesis of the acetylcholinesterase reactivator HI-6. J Chromatogr Sci 48:694–696.  https://doi.org/10.1093/chromsci/48.8.694 CrossRefPubMedGoogle Scholar
  14. Jun D, Musilova L, Pohanka M, Jung YS, Bostik P, Kuca K (2010b) Reactivation of human acetylcholinesterase and butyrylcholinesterase inhibited by leptophos-oxon with different oxime reactivators in vitro. Int J Mol Sci 11:2856–2863.  https://doi.org/10.3390/ijms11082856 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Korabecny J, Soukup O, Dolezal R, Spilovska K, Nepovimova E, Andrs M, Nguyen TD, Jun D, Musilek K, Kucerova-Chlupacova M, Kuca K (2014) From pyridinium-based to centrally active acetylcholinesterase reactivators. Mini Rev Med Chem 14:215–221.  https://doi.org/10.2174/1389557514666140219103138 CrossRefPubMedGoogle Scholar
  16. Kovarik Z, Katalinic M, Sinko G, Binder J, Holas O, Jung YS, Musilova L, Jun D, Kuca K (2010) Pseudo-catalytic scavenging: searching for a suitable reactivator of phosphorylated butyrylcholinesterase. Chem Biol Interact 187:167–171.  https://doi.org/10.1016/j.cbi.2010.02.023 CrossRefPubMedGoogle Scholar
  17. Kuca K, Cabal J (2005) Evaluation of newly synthesized reactivators of the brain cholinesterase inhibited by sarin nerve agent. Toxicol Mech Methods 15:247–252.  https://doi.org/10.1080/15376520590968770 CrossRefPubMedGoogle Scholar
  18. Kuca K, Kassa J (2003) A comparison of the ability of a new bispyridinium oxime—1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods. J Enzym Inhib Med Chem 18:529–535.  https://doi.org/10.1080/14756360310001605552 CrossRefGoogle Scholar
  19. Kuca K, Patocka J (2004) Reactivation of cyclosarin-inhibited rat brain acetylcholinesterase by pyridinium—oximes. J Enzyme Inhib Med Chem 19:39–43.  https://doi.org/10.1080/1475636031000163850 CrossRefPubMedGoogle Scholar
  20. 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 CrossRefPubMedGoogle Scholar
  21. Kuca K, Musilek K, Jun D, Zdarova-Karasova J, Nepovimova E, Soukup O, Hrabinova M, Mikler J, Franca TCC, Da Cunha EFF, De Castro AA, Valis M, Ramalho TC (2018) A newly developed oxime K203 is the most effective reactivator of tabun-inhibited acetylcholinesterase. BMC Pharmacol Toxicol 19(1):8.  https://doi.org/10.1186/s40360-018-0196-3 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Marrs TC (1993) Organophosphate poisoning. Pharmacol Therap 58:51–66.  https://doi.org/10.1016/0163-7258(93)90066-M CrossRefGoogle Scholar
  23. Masson P, Lockridge O (2010) Butyrylcholinesterase for protection from organophosphorus poisons: catalytic complexities and hysteretic behavior. Arch Biochem Biophys 494:107–120.  https://doi.org/10.1016/j.abb.2009.12.005 CrossRefPubMedGoogle Scholar
  24. Mercey G, Verdelet T, Saint-Andre G, Gillon E, Wagner A, Baati R, Jean L, Nachon F, Renard PY (2011) First efficient uncharged reactivators for the dephosphylation of poisoned human acetylcholinesterase. Chem Commun 47:5295–5297.  https://doi.org/10.1039/c1cc10787a CrossRefGoogle Scholar
  25. 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 CrossRefPubMedGoogle Scholar
  26. Musilek K, Lipka L, Racakova V, Kuca K, Jun D, Dohnal V, Dolezal M (2006) New methods in synthesis of acetylcholinesterase reactivators and evaluation of their potency to reactivate cyclosarin-inhibited AChE. Chem Pap 60:48–51.  https://doi.org/10.2478/s11696-006-0008-x CrossRefGoogle Scholar
  27. Musilek K, Jun D, Cabal J, Kassa J, Gunn-Moore F, Kuca K (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 CrossRefPubMedGoogle Scholar
  28. Musilek K, Dolezal M, Gunn-Moore F, Kuca K (2011) Design, evaluation and structure-activity relationship studies of the AChE reactivators against organophosphorus pesticides. Med Res Rev 31:548–575.  https://doi.org/10.1002/med.20192 CrossRefPubMedGoogle Scholar
  29. Nepovimova E, Korabecny J, Dolezal R, Nguyen TD, Jun D, Soukup O, Pasdiorova M, Jost P, Muckova L, Malinak D, Gorecki L, Musilek K, Kuca K (2016) A 7-methoxytacrine–4-pyridinealdoxime hybrid as a novel prophylactic agent with reactivation properties in organophosphate intoxication. Toxicol Res 5:1012–1016.  https://doi.org/10.1039/c6tx00130k CrossRefGoogle Scholar
  30. Newmark J (2004) Therapy for nerve agent poisoning. Arch Neurol 61:649–652.  https://doi.org/10.1001/archneur.61.5.649 CrossRefPubMedGoogle Scholar
  31. Rocha GB, Freire RO, Simas AM, Stewart JJP (2006) RM1: a reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. J Comput Chem 27:1101–1111.  https://doi.org/10.1002/jcc.20425 CrossRefPubMedGoogle Scholar
  32. Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem 49:3315–3321.  https://doi.org/10.1021/jm051197e CrossRefPubMedGoogle Scholar
  33. Worek F, von der Wellen J, Musilek K, Kuca K, Thiermann H (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 CrossRefPubMedGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceUniversity of Hradec KraloveHradec KraloveCzech Republic
  2. 2.College of Life ScienceYangtze UniversityJingzhouChina
  3. 3.Laboratory of Molecular Modeling Applied to the Chemical and Biological DefenseMilitary Institute of EngineeringRio de JaneiroBrazil
  4. 4.Department of ChemistryFederal University of LavrasLavrasBrazil
  5. 5.Center for Basic and Applied Research, Faculty of Informatics and ManagementUniversity of Hradec KraloveHradec KraloveCzech Republic
  6. 6.Department of Toxicology and Military Pharmacy, Faculty of Military Health PharmacyUniversity of DefenceHradec KraloveCzech Republic
  7. 7.Biomedical Research CenterUniversity Hospital Hradec KraloveHradec KraloveCzech Republic

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