Design, synthesis, in silico studies and in vitro evaluation of isatin-pyridine oximes hybrids as novel acetylcholinesterase reactivators

Autor: 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
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 1369-1376 (2021)
Druh dokumentu: article
ISSN: 1475-6366
1475-6374
14756366
DOI: 10.1080/14756366.2021.1916009
Popis: 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.
Databáze: Directory of Open Access Journals
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