In vitro evaluation of neutral oximes as reactivators of parathion-inhibited electric eel acetylcholinesterase

Joselia A. Lima; Laura P.A.N. Cavalcanti; Alcino P. Aguiar; Claudia M. Rezende; Keila S.C. Lima; Antonio L.S. Lima

doi:10.14429/dlsj.2.10723

Joselia A. Lima Dr Josélia alencar lima Master’s in Pharmacology and Experimental Therapeutics from federal University of Rio de Janeiro, in 1999 and PhD in Organic Chemistry from federal University of Rio de Janeiro, in 2006. Has experience in Pharmacological evaluation of multi-target molecules as potential inhibitors of cholinesterases and Ab disaggregating; neuroinflammation associated to Alzheimer ́s disease. Currently working as a postdoctoral scholar in the Military Institute of Engineering developing in-vitro and in vivo studies of oximes as reactivators of cholinesterases.
Laura P.A.N. Cavalcanti Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro
Alcino P. Aguiar Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro
Claudia M. Rezende Department of Organic Chemistry, Chemistry Institute, Federal University of Rio de Janeiro
Keila S.C. Lima Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro
Antonio L.S. Lima Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro

DOI: https://doi.org/10.14429/dlsj.2.10723

Keywords: acetylcholinesterase, eel AChE, reactivator, oxime, pralidoxime, parathion

Abstract

Organophosphorus (OP) compounds are irreversible inhibitors of acetylcholinesterase (AChE) commonly used as pesticides and, unfortunately, as nerve agents in terrorist attacks. These compounds are highly soluble easily crossing the blood-brain barrier (BBB). Clinically, oximes such as pralidoxime and obidoxime are used for the reactivation of AChE. These oximes are not sufficiently effective to reactivate AChE inhibited by different OPs besides the fact that they are permanently charged and do not readily cross the BBB. This work evaluated the ability of ten neutral oximes to reactivate parathion-inhibited eel AChE. Because oximes can bind to AChE as reversible inhibitors, this property was also evaluated, with pralidoxime (2-PAM) used as a reference compound. Unlike 2-PAM, which inhibited AChE in a concentration-dependent manner, neutral oximes were not good inhibitors of AChE. Neutral ligands can present affinity for the PAS site. Neutral oximes 1 and 2 (200 mM) reactivated parathion-inhibited eel AChE by 9% and 11%, respectively; but neither of them surpassed the reactivation efficacy of 2-PAM (25%). Neutral oximes 1 and 2 reactivated AChE at a safe concentration for humans. Both neutral oximes 1 and 2 are good non-quaternary moieties for the synthesis of conjugates with enhanced reactivation potency and BBB penetration.

Author Biographies

Joselia A. Lima, Dr Josélia alencar lima Master’s in Pharmacology and Experimental Therapeutics from federal University of Rio de Janeiro, in 1999 and PhD in Organic Chemistry from federal University of Rio de Janeiro, in 2006. Has experience in Pharmacological evaluation of multi-target molecules as potential inhibitors of cholinesterases and Ab disaggregating; neuroinflammation associated to Alzheimer ́s disease. Currently working as a postdoctoral scholar in the Military Institute of Engineering developing in-vitro and in vivo studies of oximes as reactivators of cholinesterases.

Dr Josélia Alencar Lima Master’s in Pharmacology and Experimental Therapeutics from Federal University of Rio de Janeiro, in 1999 and PhD in Organic Chemistry from Federal University of Rio de Janeiro, in 2006. Has experience in Pharmacological evaluation of multi-target molecules as potential inhibitors of cholinesterases and Ab disaggregating; neuroinflammation associated to Alzheime´s disease. Currently working as a postdoctoral scholar in the Military Institute of Engineering developing in-vitro and in vivo studies of oximes as reactivators of cholinesterases.

Laura P.A.N. Cavalcanti, Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro

Mr Laura P.A.N. Cavalcanti holds a degree in Chemical Processes from the Federal Institute of Education, Science and Technology of Rio de Janeiro, in 2010 and a Master’s in Chemistry from the Military Institute of Engineering (Concentration Area: Physico-chemical / Spectrometry), in 2015. Has experience in the field of Chemistry in the following subjects: Analytical chemistry, organic chemistry, environmental chemistry, medicinal chemistry and spectrometry. Actually is a doctorate student in the Natural Products Research Institute of Federal University of Rio de Janeiro.

Alcino P. Aguiar, Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro

Mr Alcino Palermo de Aguiar received his DSc in Chemistry, in 1996 from the Federal University of Rio de Janeiro, Brazil. He began work at Military Institute of Engineering, in 1998, today is Associated Professor. His scientific interests are directed towards the development of new methodologies for the introduction of carbon-carbon bond using reagent with low toxicity and low cost, synthesis of heterocycles with biological activity, regio- and estereoselective synthesis, organic reaction mechanism and polymer synthesis for ambiental application. He has expertise in structural characterisation of organic compound using physical methods as NMR, FTIR, MS.

Claudia M. Rezende, Department of Organic Chemistry, Chemistry Institute, Federal University of Rio de Janeiro

Claudia M. Rezende is a Chemistry and Associate Professor at Institute of Chemistry, Federal University of Rio de Janeiro. Coordinated the postgraduation in Organic Chemistry at UFRJ and carries out her research in Aroma Chemistry; Secondary metabolites for essences and biological activity; Gas chromatography, gas chromatography-olfactometry; liquid chromatography and mass spectrometry. Board of the Brazilian Chemical Society (SBQ 2008-14) as first secretary , treasurer and vice president. Financial director of the Brazilian Society of Mass Spectrometry (BRMass 2014-16) and now vice-president. Coordinated, in 2011, the International Year of Chemistry - Brazil through SBQ

Keila S.C. Lima, Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro

Dr Keila dos Santos Cople Lima received Master’s from the Federal University of Rio de Janeiro, in 1996 and PhD from the Federal Rural University of Rio de Janeiro, in 2006. She is currently a professor of the Postgraduate Program in Biological Defense of the Institute of Biology of the Army (IBEx). Has experience in the area of Biotechnology, working mainly in the following subjects: gamma radiation, chromatography, mass spectrometry, natural products, aroma, proteomics and metabolomics.

Antonio L.S. Lima, Military Institute of Engineering, Chemical and Biological Defence Laboratory, Rio de Janeiro

Dr Antonio Luís dos Santos Lima received Master’s degree in Chemistry from the Military Engineering Institute, in 2000 and PhD in Organic Chemistry from the Federal University of Rio de Janeiro, in 2007. Professor of the Military Engineering Institute, Coordinator of the Materials Projects for Defense and Research of the Program in Biological Defense of the Institute of Biology of the Army (IBEx). Experience in the field of Chemistry, with emphasis on Organic and Analytical Chemistry, working mainly on the following topics: gas and liquid chromatography, mass spectrometry, nuclear magnetic resonance, natural products, toxins and antidotes.

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