Sodium borohydride and thiol mediated nitrite release from nitroaromatic antibiotics.
Bioorg Med Chem Lett
; 48: 128245, 2021 09 15.
Article
em En
| MEDLINE
| ID: mdl-34242759
ABSTRACT
Nitroaromatic antibiotics are used to treat a variety of bacterial and parasitic infections. These prodrugs require reductive bioactivation for activity, which provides a pathway for the release of nitrogen oxide species such as nitric oxide, nitrite, and/or nitroxyl. Using sodium borohydride and 2-aminoethanol as model reductants, this work examines release of nitrogen oxide species from various nitroaromatic compounds through several characterization methods. Specifically, 4- and 5-nitroimidazoles reproducibly generate higher amounts of nitrite (not nitric oxide or nitroxyl) than 2-nitroimidazoles during the reaction of model hydride donors or thiols. Mass spectrometric analysis shows clean formation of products resulting from nucleophile addition and nitro group loss. 2-Nitrofurans generate nitrite upon addition of sodium borohydride or 2-aminoethanethiol, but these complex reactions do not produce clean organic products. A mechanism that includes nucleophile addition to the carbon ßto the nitro group to generate a nitronate anion followed by protonation and nitrous acid elimination explains the observed products and labeling studies. These systematic studies give a better understanding of the release mechanisms of nitrogen oxide species from these compounds allowing for the design of more efficient therapeutics.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Sulfidrila
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Boroidretos
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Antibacterianos
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Nitritos
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Nitrocompostos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article