ArticleJournal of the American Chemical Society2013
Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32 citing papers in PubMed, 83 citations in OpenAlex.
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- Exploring the Natural Products Atlas (NPAtlas) Database for Hunting Prospective Irreversible Covalent DprE1 Inhibitors With Antitubercular Activity: An IntegratedJournal of tropical medicine · 2026Article
- In-Silico Exploration of the StreptomeDB Database for Potential Irreversible DprE1 Inhibitors toward Antitubercular Treatment.ChemistryOpen · 2025Article
- Fighting Antimicrobial Resistance: Innovative Drugs in Antibacterial Research.Angewandte Chemie (International ed. in English) · 2025Review
- Review
- Recent Advances of DprE1 Inhibitors againstACS omega · 2022Review
- BTZ-Derived Benzisothiazolinones with In Vitro Activity againstACS medicinal chemistry letters · 2022Article
- Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening.Acta pharmacologica Sinica · 2022Article
- New Insight into Dearomatization and Decarbonylation of Antitubercular 4H-Benzo[e][1,3]thiazinones: Stable 5H- and 7H-Benzo[e][1,3]thiazines.ChemMedChem · 2022Article
- Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity.International journal of molecular sciences · 2021Review
- Nitroaromatic Antibiotics as Nitrogen Oxide Sources.Biomolecules · 2021Review
- Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis.EMBO molecular medicine · 2021Article
- 8-cyanobenzothiazinone analogs with potent antitubercular activity.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2021Article
- Hydride-induced Meisenheimer complex formation reflects activity of nitro aromatic anti-tuberculosis compounds.RSC medicinal chemistry · 2021Article
- Recent Progress in the Discovery and Development of 2-Nitroimidazooxazines and 6-Nitroimidazooxazoles to Treat Tuberculosis and Neglected Tropical Diseases.Molecules (Basel, Switzerland) · 2020Review
- Crystallographic evidence for unintended benzisothiazolinone 1-oxide formation from benzothiazinones through oxidation.Acta crystallographica. Section C, Structural chemistry · 2020Article
- [2-Chloro-3-nitro-5-(tri-fluoro-meth-yl)phen-yl](piperidin-1-yl)methanone: structural characterization of a side product in benzo-thia-zinone synthesis.Acta crystallographica. Section E, Crystallographic communications · 2020Article
- Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds.PloS one · 2020Article
- Deuteration of BTZ043 Extends the Lifetime of Meisenheimer Intermediates to the Antituberculosis Nitroso Oxidation State.ACS medicinal chemistry letters · 2019Article
- Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1.Scientific reports · 2018Article
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8 authors at 1 institution in 1 country.
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Abstract
The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitroaromatic compounds, including 1,3-benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2' oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron-deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitroaromatic compounds synthesized by us and others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide, and hydride induce nonenzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron-deficient aromatic carbon present in these compounds. Furthermore, we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypothesis for the mechanism of action of nitroaromatic anti-TB agents, in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1.
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