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Rice AM, Faig A, Wolff DE, et al. Sodium borohydride and thiol mediated nitrite release from nitroaromatic antibiotics. Bioorg Med Chem Lett. 2021;48:128245doi: 10.1016/j.bmcl.2021.128245.
Rice, A. M., Faig, A., Wolff, D. E., & King, S. B. (2021). Sodium borohydride and thiol mediated nitrite release from nitroaromatic antibiotics. Bioorganic & medicinal chemistry letters, 48128245. https://doi.org/10.1016/j.bmcl.2021.128245
Rice, Allison M, et al. "Sodium borohydride and thiol mediated nitrite release from nitroaromatic antibiotics." Bioorganic & medicinal chemistry letters vol. 48 (2021): 128245. doi: https://doi.org/10.1016/j.bmcl.2021.128245
Rice AM, Faig A, Wolff DE, King SB. Sodium borohydride and thiol mediated nitrite release from nitroaromatic antibiotics. Bioorg Med Chem Lett. 2021 Sep 15;48:128245. doi: 10.1016/j.bmcl.2021.128245. Epub 2021 Jul 07. PMID: 34242759.
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Bioorg Med Chem Lett. 2021 Sep 15;48:128245. doi: 10.1016/j.bmcl.2021.128245. Epub 2021 Jul 07.

Sodium borohydride and thiol mediated nitrite release from nitroaromatic antibiotics.

Bioorganic & medicinal chemistry letters

Allison M Rice, Allison Faig, David E Wolff, S Bruce King

Affiliations

  1. Wake Forest University, Department of Chemistry, Winston-Salem, NC 27101, United States of America.
  2. Wake Forest University, Department of Chemistry, Winston-Salem, NC 27101, United States of America. Electronic address: [email protected].

PMID: 34242759 DOI: 10.1016/j.bmcl.2021.128245

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 βto 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.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Keywords: Metronidazole; Nitrite; Nitroaromatic antibiotics; PA-824; Reactive nitrogen species (RNS)

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