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Synthesis and in vitro evaluation of bis-quaternary 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide derivatives as reactivators against sarin and VX inhibited human acetylcholinesterase (hAChE)
Institution:1. Department of Recombinant Vaccines, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk, Poland;2. Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, Krzywoustego 4, 44-101 Gliwice, Poland;3. Department of Virus Molecular Biology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk, Poland;4. Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland;1. N.D. Zelinsky Institute of Organic Chemistry, Leninsky Prospect, 47, Moscow 119991, Russia;2. Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India;3. Department of Chemistry, University of Mysore, Manasagangotri, Mysore 560001, India;4. Department of Biotechnology, Sri Jayachamarajendra College of Engineering, JSS, Technical Institutions Campus, Mysore 570006, India;1. Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, 08028 Barcelona, Spain;2. Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom;3. Bradford School of Pharmacy, University of Bradford, West Yorkshire BD7 1 DP, United Kingdom;4. Department of Pharmaceutics, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana;5. Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain;1. Alchemical Research, LLC, 260 East Wall Street, Bethlehem, PA 18018, USA;2. Division of Pharmaceutical Sciences, School of Pharmacy, and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA;1. School of Pharmacy, Health Sciences Campus, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1;2. Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Abstract:A series of bis-quaternary pyridinium derivatives 3a3i of 2-(hydroxyimino)-N-(pyridin-3-yl)acetamide (2) have been synthesized. The synthesized pyridinium compounds have an amide group in conjugation to the oxime moiety. These compounds were evaluated in vitro for their reactivation efficacy against organophosphorus (OP) nerve agents (NAs) (sarin and VX) inhibited human erythrocyte ghost acetylcholinesterase (hAChE) and compared with the reactivation efficacy of 2-PAM and obidoxime. The pKa values of the synthesized compounds were found closer to the pKa values of 2- and 4-pyridinium oxime reactivators such as 2-PAM and obidoxime. Some of the compounds have shown better reactivation efficacy than 2-PAM, and obidoxime against sarin and VX inhibited AChE.
Keywords:Acetylcholinesterase  Organophosphorus  Nerve agents  Reactivators
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