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.

Biomedical Research Centre University Hospital in Hradec Kralove Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic

Department of Toxicology and Military Pharmacy Faculty of Military Health Sciences University of Defence Hradec Kralove Czech Republic

Faculty of Informatics and Management Center for Basic and Applied Research University of Hradec Kralove Hradec Kralove Czech Republic

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Starke K. Presynaptic receptors. Annu Rev Pharmacol Toxicol 1981;21:7–30. PubMed

Dolezal R, Korabecny J, Malinak D, et al. . Ligand-based 3D QSAR analysis of reactivation potency of mono-and bis-pyridinium aldoximes toward VX-inhibited rat acetylcholinesterase. J Mol Graph 2015;56:113–29. PubMed

Moshiri M, Darchini-Maragheh E, Balali-Mood M.. Advances in toxicology and medical treatment of chemical warfare nerve agents. Daru 2012;20:81. PubMed PMC

Musilek K, Dolezal M, Gunn‐Moore F, et al. . Design, evaluation and structure—Activity relationship studies of the AChE reactivators against organophosphorus pesticides. Med Res Rev 2011;31:548–75. PubMed

Watson A, Opresko D, Young RA, et al. . Organophosphate nerve agents. Handbook of toxicology of chemical warfare agents. 2nd ed. London: Handbook of Toxicology of Chemical Warfare Agents; 2009.

Žunec S, Radić B, Kuča K, et al. . Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning/Usporedno određivanje učinkovitosti bispiridinijevih oksima pri trovanju paraoksonom. Arh Hig Rada Toksikol 2015;66:129–34. PubMed

Kassa J. Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J Toxicol Clin Toxicol 2002;40:803–16. PubMed

Gorecki L, Korabecny J, Musilek K, et al. . SAR study to find optimal cholinesterase reactivator against organophosphorous nerve agents and pesticides. Arch Toxicol 2016;90:2831–59. PubMed

Sharma R, Gupta B, Singh N, et al. . Development and structural modifications of cholinesterase reactivators against chemical warfare agents in last decade: a review. Mini-Rev Med Chem 2015;15:58–72. PubMed

Kassa J, Misik J, Karasova JZ.. A comparison of the potency of a novel bispyridinium oxime K203 and currently available oximes (obidoxime, HI‐6) to counteract the acute neurotoxicity of sarin in rats. Basic Clin Pharmacol Toxicol 2012;111:333–8. PubMed

Musilova L, Kuca K, Jung Y-S, et al. . In vitro oxime-assisted reactivation of paraoxon-inhibited human acetylcholinesterase and butyrylcholinesterase. Clin Toxicol 2009;47:545–50. PubMed

Gorecki L, Andrys R, Schmidt M, et al. . Cysteine-targeted insecticides against A. gambiae acetyl-cholinesterase are neither selective nor reversible inhibitors. ACS Med Chem Lett in press. doi: 10.1021/acsmedchemlett.9b00477 PubMed DOI PMC

Ellman GL, Courtney KD, Jr, Andres V, et al. . A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961;7:88–95. PubMed

Worek F, Thiermann H, Szinicz L, et al. . Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes. Biochem Pharmacol 2004;68:2237–48. PubMed

Worek F, Wille T, Aurbek N, et al. . Reactivation of organophosphate-inhibited human, Cynomolgus monkey, swine and guinea pig acetylcholinesterase by MMB-4: a modified kinetic approach. Toxicol Appl Pharmacol 2010;249:231–7. PubMed

Worek F, von der Wellen J, Musilek K, et al. . Reactivation kinetics of a homologous series of bispyridinium bis-oximes with nerve agent-inhibited human acetylcholinesterase. Arch Toxicol 2012;86:1379–86. PubMed

Musilek K, Komloova M, Holas O, et al. . Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage–implications for early Myasthenia gravis treatment. Eur J Med Chem 2011;46:811–8. PubMed

Zorbaz T, Malinak D, Maraković N, et al. . 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 2018;61:10753–66. PubMed

Chennamaneni SR, Vobalaboina V, Garlapati A.. Quaternary salts of 4, 3′ and 4, 4′ bis-pyridinium monooximes: synthesis and biological activity. Bioorg Med Chem Lett 2005;15:3076–80. PubMed

Sussman JL, Harel M, Frolow F, et al. . Atomic-structure of acetylcholinesterase from torpedo-californica – A prototypic acetylcholine-binding protein. Science 1991;253:872–9. PubMed

Bajda M, Więckowska A, Hebda M, et al. . Structure-based search for new inhibitors of cholinesterases. Int J Mol Sci 2013;14:5608–32. PubMed PMC

Bajgar J, Fusek J, Kuca K, et al. . Treatment of organophosphate intoxication using cholinesterase reactivators: facts and fiction. Mini-Rev Med Chem 2007;7:461–6. PubMed

Kovarik Z, Katalinić M, Šinko G, et al. . Pseudo-catalytic scavenging: searching for a suitable reactivator of phosphorylated butyrylcholinesterase. Chem-Biol Interact 2010;187:167–71. PubMed

Trott O, Olson AJ.. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010;31:455–61. PubMed PMC

Allgardsson A, Berg L, Akfur C, et al. . Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6. Proc Natl Acad Sci USA 2016;113:5514–9. PubMed PMC

Gorecki L, Soukup O, Kucera T, et al. . Oxime K203: a drug candidate for the treatment of tabun intoxication. Arch Toxicol 2019;93:673–91. PubMed

Zhang YK, Kua J, McCammon JA.. Role of the catalytic triad and oxyanion hole in acetylcholinesterase catalysis: an ab initio QM/MM study. J Am Chem Soc 2002;124:10572–7. PubMed

Driant T, Nachon F, Ollivier C, et al. . On the influence of the protonation states of active site residues on AChE reactivation: a QM/MM approach. ChemBioChem 2017;18:666–75. PubMed

Giacoppo JOS, Franca TCC, Kuca K, et al. . Molecular modeling and in vitro reactivation study between the oxime BI-6 and acetylcholinesterase inhibited by different nerve agents. J Biomol Struct Dyn 2015;33:2048–58. PubMed

Charged pyridinium oximes with thiocarboxamide moiety are equally or less effective reactivators of organophosphate-inhibited cholinesterases compared to analogous carboxamides

Development of versatile and potent monoquaternary reactivators of acetylcholinesterase

Molecular Modeling Studies on the Multistep Reactivation Process of Organophosphate-Inhibited Acetylcholinesterase and Butyrylcholinesterase

Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy