Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
- 31 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Archives of Toxicology
- Vol. 95 (3), 985-1001
- https://doi.org/10.1007/s00204-021-02981-w
Abstract
To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.Keywords
Funding Information
- Ministerstvo Zdravotnictví Ceské Republiky (17-32801A)
- Long-term development plan
- University of Hradec Kralove (VT2019-2021)
- French Ministry of Armed Forces (NBC-5-C-4210)
This publication has 66 references indexed in Scilit:
- GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkitBioinformatics, 2013
- ACPYPE - AnteChamber PYthon Parser interfacEBMC Research Notes, 2012
- R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragmentsNucleic Acids Research, 2011
- Direct C−H Arylation of Electron-Deficient Heterocycles with Arylboronic AcidsJournal of the American Chemical Society, 2010
- Features and development of CootActa crystallographica. Section D, Structural biology, 2010
- electronic Ligand Builder and Optimization Workbench(eLBOW): a tool for ligand coordinate and restraint generationActa crystallographica. Section D, Structural biology, 2009
- The global distribution of fatal pesticide self-poisoning: Systematic reviewBMC Public Health, 2007
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- Development and testing of a general amber force fieldJournal of Computational Chemistry, 2004
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996