Cargando…
New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds
For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure sinc...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151989/ https://www.ncbi.nlm.nih.gov/pubmed/28737687 http://dx.doi.org/10.3390/molecules22071234 |
_version_ | 1783357269831843840 |
---|---|
author | Katalinić, Maja Zandona, Antonio Ramić, Alma Zorbaz, Tamara Primožič, Ines Kovarik, Zrinka |
author_facet | Katalinić, Maja Zandona, Antonio Ramić, Alma Zorbaz, Tamara Primožič, Ines Kovarik, Zrinka |
author_sort | Katalinić, Maja |
collection | PubMed |
description | For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was proven to fit the cholinesterases active site and reversibly inhibit their activity. Three Cinchona oximes (C1, C2, and C3), derivatives of the 9-oxocinchonidine, were synthesized and investigated in reactivation of various OP-inhibited AChE and BChE. As the results showed, the tested oximes were more efficient in the reactivation of BChE and they reactivated enzyme activity to up to 70% with reactivation rates similar to known pyridinium oximes used as antidotes in medical practice today. Furthermore, the oximes showed selectivity towards binding to the BChE active site and the determined enzyme-oxime dissociation constants supported work on the future development of inhibitors in other targeted studies (e.g., in treatment of neurodegenerative disease). Also, we monitored the cytotoxic effect of Cinchona oximes on two cell lines Hep G2 and SH-SY5Y to determine the possible limits for in vivo application. The cytotoxicity results support future studies of these compounds as long as their biological activity is targeted in the lower micromolar range. |
format | Online Article Text |
id | pubmed-6151989 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-61519892018-11-13 New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds Katalinić, Maja Zandona, Antonio Ramić, Alma Zorbaz, Tamara Primožič, Ines Kovarik, Zrinka Molecules Article For the last six decades, researchers have been focused on finding efficient reactivators of organophosphorus compound (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study, we have focused our research on a new oxime scaffold based on the Cinchona structure since it was proven to fit the cholinesterases active site and reversibly inhibit their activity. Three Cinchona oximes (C1, C2, and C3), derivatives of the 9-oxocinchonidine, were synthesized and investigated in reactivation of various OP-inhibited AChE and BChE. As the results showed, the tested oximes were more efficient in the reactivation of BChE and they reactivated enzyme activity to up to 70% with reactivation rates similar to known pyridinium oximes used as antidotes in medical practice today. Furthermore, the oximes showed selectivity towards binding to the BChE active site and the determined enzyme-oxime dissociation constants supported work on the future development of inhibitors in other targeted studies (e.g., in treatment of neurodegenerative disease). Also, we monitored the cytotoxic effect of Cinchona oximes on two cell lines Hep G2 and SH-SY5Y to determine the possible limits for in vivo application. The cytotoxicity results support future studies of these compounds as long as their biological activity is targeted in the lower micromolar range. MDPI 2017-07-22 /pmc/articles/PMC6151989/ /pubmed/28737687 http://dx.doi.org/10.3390/molecules22071234 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Katalinić, Maja Zandona, Antonio Ramić, Alma Zorbaz, Tamara Primožič, Ines Kovarik, Zrinka New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds |
title | New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds |
title_full | New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds |
title_fullStr | New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds |
title_full_unstemmed | New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds |
title_short | New Cinchona Oximes Evaluated as Reactivators of Acetylcholinesterase and Butyrylcholinesterase Inhibited by Organophosphorus Compounds |
title_sort | new cinchona oximes evaluated as reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by organophosphorus compounds |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151989/ https://www.ncbi.nlm.nih.gov/pubmed/28737687 http://dx.doi.org/10.3390/molecules22071234 |
work_keys_str_mv | AT katalinicmaja newcinchonaoximesevaluatedasreactivatorsofacetylcholinesteraseandbutyrylcholinesteraseinhibitedbyorganophosphoruscompounds AT zandonaantonio newcinchonaoximesevaluatedasreactivatorsofacetylcholinesteraseandbutyrylcholinesteraseinhibitedbyorganophosphoruscompounds AT ramicalma newcinchonaoximesevaluatedasreactivatorsofacetylcholinesteraseandbutyrylcholinesteraseinhibitedbyorganophosphoruscompounds AT zorbaztamara newcinchonaoximesevaluatedasreactivatorsofacetylcholinesteraseandbutyrylcholinesteraseinhibitedbyorganophosphoruscompounds AT primozicines newcinchonaoximesevaluatedasreactivatorsofacetylcholinesteraseandbutyrylcholinesteraseinhibitedbyorganophosphoruscompounds AT kovarikzrinka newcinchonaoximesevaluatedasreactivatorsofacetylcholinesteraseandbutyrylcholinesteraseinhibitedbyorganophosphoruscompounds |