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Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon

Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited ACh...

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Autores principales: Kuca, Kamil, Jun, Daniel, Junova, Lucie, Musilek, Kamil, Hrabinova, Martina, da Silva, Jorge Alberto Valle, Ramalho, Teodorico Castro, Valko, Marian, Wu, Qinghua, Nepovimova, Eugenie, França, Tanos Celmar Costa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100540/
https://www.ncbi.nlm.nih.gov/pubmed/29735900
http://dx.doi.org/10.3390/molecules23051103
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author Kuca, Kamil
Jun, Daniel
Junova, Lucie
Musilek, Kamil
Hrabinova, Martina
da Silva, Jorge Alberto Valle
Ramalho, Teodorico Castro
Valko, Marian
Wu, Qinghua
Nepovimova, Eugenie
França, Tanos Celmar Costa
author_facet Kuca, Kamil
Jun, Daniel
Junova, Lucie
Musilek, Kamil
Hrabinova, Martina
da Silva, Jorge Alberto Valle
Ramalho, Teodorico Castro
Valko, Marian
Wu, Qinghua
Nepovimova, Eugenie
França, Tanos Celmar Costa
author_sort Kuca, Kamil
collection PubMed
description Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.
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spelling pubmed-61005402018-11-13 Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon Kuca, Kamil Jun, Daniel Junova, Lucie Musilek, Kamil Hrabinova, Martina da Silva, Jorge Alberto Valle Ramalho, Teodorico Castro Valko, Marian Wu, Qinghua Nepovimova, Eugenie França, Tanos Celmar Costa Molecules Article Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results. MDPI 2018-05-07 /pmc/articles/PMC6100540/ /pubmed/29735900 http://dx.doi.org/10.3390/molecules23051103 Text en © 2018 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
Kuca, Kamil
Jun, Daniel
Junova, Lucie
Musilek, Kamil
Hrabinova, Martina
da Silva, Jorge Alberto Valle
Ramalho, Teodorico Castro
Valko, Marian
Wu, Qinghua
Nepovimova, Eugenie
França, Tanos Celmar Costa
Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon
title Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon
title_full Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon
title_fullStr Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon
title_full_unstemmed Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon
title_short Synthesis, Biological Evaluation, and Docking Studies of Novel Bisquaternary Aldoxime Reactivators on Acetylcholinesterase and Butyrylcholinesterase Inhibited by Paraoxon
title_sort synthesis, biological evaluation, and docking studies of novel bisquaternary aldoxime reactivators on acetylcholinesterase and butyrylcholinesterase inhibited by paraoxon
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100540/
https://www.ncbi.nlm.nih.gov/pubmed/29735900
http://dx.doi.org/10.3390/molecules23051103
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