Experimental hydrophilic reactivator: bisoxime with three positive charges
- 28 Downloads
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).
KeywordsReactivator Oxime AChE Nerve agent Docking study
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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