Design, Synthesis, Studies and Evaluation of Isatin-pyridine Oximes Hybrids As Novel Acetylcholinesterase Reactivators

Overview

Journal J Enzyme Inhib Med Chem

Specialty Biochemistry

Date 2021 Jun 21

PMID 34148470

Citations 3

Authors

Daniel A S Kitagawa

Rafael B Rodrigues

Thiago N Silva

Wellington V Dos Santos

Vinicius C V da Rocha

Joyce S F D de Almeida

Leandro B Bernardo

Taynara Carvalho-Silva

Cintia N Ferreira

Angelo A T da Silva

Alessandro B C Simas

Eugenie Nepovimova

Kamil Kuca

Tanos C C Franca

Samir F de A Cavalcante

Affiliations

Soon will be listed here.

Abstract

Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable reactivation also pointed by the studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.

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References

Sit R, Radic Z, Gerardi V, Zhang L, Garcia E, Katalinic M . New structural scaffolds for centrally acting oxime reactivators of phosphylated cholinesterases. J Biol Chem. 2011; 286(22):19422-30. PMC: 3103321. DOI: 10.1074/jbc.M111.230656. View

Chauhan G, Pathak D, Ali F, Bhutani R, Kapoor G, Khasimbi S . Advances in Synthesis, Derivatization and Bioactivity of Isatin: A Review. Curr Org Synth. 2020; 18(1):37-74. DOI: 10.2174/1570179417666200924150907. View

Garcia G, Campbell A, Olson J, Moorad-Doctor D, Morthole V . Novel oximes as blood-brain barrier penetrating cholinesterase reactivators. Chem Biol Interact. 2010; 187(1-3):199-206. DOI: 10.1016/j.cbi.2010.02.033. View

Gorecki L, Korabecny J, Musilek K, Nepovimova E, Malinak D, Kucera T . Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006-2016). Expert Opin Ther Pat. 2017; 27(9):971-985. DOI: 10.1080/13543776.2017.1338275. View

Costanzi S, Machado J, Mitchell M . Nerve Agents: What They Are, How They Work, How to Counter Them. ACS Chem Neurosci. 2018; 9(5):873-885. DOI: 10.1021/acschemneuro.8b00148. View

Oh K, Yang G, Jun D, Kuca K, Jung Y . Bis-pyridiumaldoxime reactivators connected with CH2O(CH2)n OCH2 linkers between pyridinium rings and their reactivity against VX. Bioorg Med Chem Lett. 2006; 16(18):4852-5. DOI: 10.1016/j.bmcl.2006.06.063. View

Worek F, Wille T, Koller M, Thiermann H . Toxicology of organophosphorus compounds in view of an increasing terrorist threat. Arch Toxicol. 2016; 90(9):2131-2145. DOI: 10.1007/s00204-016-1772-1. View

Dvir H, Silman I, Harel M, Rosenberry T, Sussman J . Acetylcholinesterase: from 3D structure to function. Chem Biol Interact. 2010; 187(1-3):10-22. PMC: 2894301. DOI: 10.1016/j.cbi.2010.01.042. View

Worek F, Reiter G, Eyer P, Szinicz L . Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch Toxicol. 2002; 76(9):523-9. DOI: 10.1007/s00204-002-0375-1. View

10.

Kitagawa D, Cavalcante S, de Paula R, Rodrigues R, Bernardo L, da Silva M . In Vitro Evaluation of Neutral Aryloximes as Reactivators for Acetylcholinesterase Inhibited by Paraoxon. Biomolecules. 2019; 9(10). PMC: 6843506. DOI: 10.3390/biom9100583. View

11.

Carletti E, Colletier J, Dupeux F, Trovaslet M, Masson P, Nachon F . Structural evidence that human acetylcholinesterase inhibited by tabun ages through O-dealkylation. J Med Chem. 2010; 53(10):4002-8. DOI: 10.1021/jm901853b. View

12.

Jokanovic M, Stojiljkovic M . Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning. Eur J Pharmacol. 2006; 553(1-3):10-7. DOI: 10.1016/j.ejphar.2006.09.054. View

13.

Sit R, Fokin V, Amitai G, Sharpless K, Taylor P, Radic Z . Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification. J Med Chem. 2014; 57(4):1378-89. PMC: 4167068. DOI: 10.1021/jm401650z. View

14.

Franca T, Kitagawa D, Cavalcante S, da Silva J, Nepovimova E, Kuca K . Novichoks: The Dangerous Fourth Generation of Chemical Weapons. Int J Mol Sci. 2019; 20(5). PMC: 6429166. DOI: 10.3390/ijms20051222. View

15.

Meek E, Chambers H, Coban A, Funck K, Pringle R, Ross M . Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates. Toxicol Sci. 2012; 126(2):525-33. DOI: 10.1093/toxsci/kfs013. View

16.

Thomsen R, Christensen M . MolDock: a new technique for high-accuracy molecular docking. J Med Chem. 2006; 49(11):3315-21. DOI: 10.1021/jm051197e. View

17.

Cavalcante S, Kitagawa D, Rodrigues R, Bernardo L, da Silva T, Dos Santos W . Synthesis and in vitro evaluation of neutral aryloximes as reactivators of Electrophorus eel acetylcholinesterase inhibited by NEMP, a VX surrogate. Chem Biol Interact. 2019; 309:108682. DOI: 10.1016/j.cbi.2019.05.048. View

18.

Chambers J, Chambers H, Meek E, Pringle R . Testing of novel brain-penetrating oxime reactivators of acetylcholinesterase inhibited by nerve agent surrogates. Chem Biol Interact. 2012; 203(1):135-8. DOI: 10.1016/j.cbi.2012.10.017. View

19.

Radic Z, Kalisiak J, Fokin V, Sharpless K, Taylor P . Interaction kinetics of oximes with native, phosphylated and aged human acetylcholinesterase. Chem Biol Interact. 2010; 187(1-3):163-6. PMC: 2912944. DOI: 10.1016/j.cbi.2010.04.014. View

20.

Soukup O, Jun D, Tobin G, Kuca K . The summary on non-reactivation cholinergic properties of oxime reactivators: the interaction with muscarinic and nicotinic receptors. Arch Toxicol. 2012; 87(4):711-9. DOI: 10.1007/s00204-012-0977-1. View