Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators
Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organop...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2021.1916009 |
| _version_ | 1818332567134273536 |
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| author | Daniel A. S. Kitagawa Rafael B. Rodrigues Thiago N. Silva Wellington V. dos Santos Vinicius C. V. da Rocha Joyce S. F. D. de Almeida Leandro B. Bernardo Taynara Carvalho-Silva Cintia N. Ferreira Angelo A. T. da Silva Alessandro B. C. Simas Eugenie Nepovimova Kamil Kuča Tanos C. C. França Samir F. de A. Cavalcante |
| author_facet | Daniel A. S. Kitagawa Rafael B. Rodrigues Thiago N. Silva Wellington V. dos Santos Vinicius C. V. da Rocha Joyce S. F. D. de Almeida Leandro B. Bernardo Taynara Carvalho-Silva Cintia N. Ferreira Angelo A. T. da Silva Alessandro B. C. Simas Eugenie Nepovimova Kamil Kuča Tanos C. C. França Samir F. de A. Cavalcante |
| author_sort | Daniel A. S. Kitagawa |
| collection | DOAJ |
| description | Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning. |
| first_indexed | 2024-12-13T13:37:47Z |
| format | Article |
| id | doaj.art-64caf545eedf4c7299e2546a21467177 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-13T13:37:47Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-64caf545eedf4c7299e2546a214671772022-12-21T23:43:41ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742021-01-013611369137610.1080/14756366.2021.19160091916009Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivatorsDaniel A. S. Kitagawa0Rafael B. Rodrigues1Thiago N. Silva2Wellington V. dos Santos3Vinicius C. V. da Rocha4Joyce S. F. D. de Almeida5Leandro B. Bernardo6Taynara Carvalho-Silva7Cintia N. Ferreira8Angelo A. T. da Silva9Alessandro B. C. Simas10Eugenie Nepovimova11Kamil Kuča12Tanos C. C. França13Samir F. de A. Cavalcante14Laboratory of Molecular Modelling Applied to Chemical and Biological Defense (LMACBD), Military Institute of Engineering (IME)Brazilian Army Technological Center (CTEx), Institute of CBRN Defense (IDQBRN)School of Pharmacy, Universidade Castelo Branco (UCB)Emergency and Rescue Department (DSE), Rio de Janeiro State Fire Department (CBMERJ)Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro,Laboratory of Molecular Modelling Applied to Chemical and Biological Defense (LMACBD), Military Institute of Engineering (IME)Brazilian Army Technological Center (CTEx), Institute of CBRN Defense (IDQBRN)Brazilian Army Technological Center (CTEx), Institute of CBRN Defense (IDQBRN)Brazilian Army Technological Center (CTEx), Institute of CBRN Defense (IDQBRN)Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro,Instituto de Pesquisas de Produtos Naturais Walter Mors (IPPN), Universidade Federal do Rio de Janeiro (UFRJ)Department of Chemistry, Faculty of Science, University of Hradec KrálovéDepartment of Chemistry, Faculty of Science, University of Hradec KrálovéLaboratory of Molecular Modelling Applied to Chemical and Biological Defense (LMACBD), Military Institute of Engineering (IME)Brazilian Army Technological Center (CTEx), Institute of CBRN Defense (IDQBRN)Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.http://dx.doi.org/10.1080/14756366.2021.1916009isatinpyridine oximesorganophosphorus poisoningcholinesterase reactivatorsnerve agentsantidotes |
| spellingShingle | Daniel A. S. Kitagawa Rafael B. Rodrigues Thiago N. Silva Wellington V. dos Santos Vinicius C. V. da Rocha Joyce S. F. D. de Almeida Leandro B. Bernardo Taynara Carvalho-Silva Cintia N. Ferreira Angelo A. T. da Silva Alessandro B. C. Simas Eugenie Nepovimova Kamil Kuča Tanos C. C. França Samir F. de A. Cavalcante Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators Journal of Enzyme Inhibition and Medicinal Chemistry isatin pyridine oximes organophosphorus poisoning cholinesterase reactivators nerve agents antidotes |
| title | Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators |
| title_full | Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators |
| title_fullStr | Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators |
| title_full_unstemmed | Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators |
| title_short | Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators |
| title_sort | design synthesis in silico studies and in vitro evaluation of isatin pyridine oximes hybrids as novel acetylcholinesterase reactivators |
| topic | isatin pyridine oximes organophosphorus poisoning cholinesterase reactivators nerve agents antidotes |
| url | http://dx.doi.org/10.1080/14756366.2021.1916009 |
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