title: Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents.
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.
authors: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
authors: Rohit
authors: R
authors: Tiwari
authors: Garrett C
authors: GC
authors: Moraski
authors: Viktor
authors: V
authors: Krchňák
authors: Patricia A
authors: PA
authors: Miller
authors: Mariangelli
authors: M
authors: Colon-Martinez
authors: Eliza
authors: E
authors: Herrero
authors: Allen G
authors: AG
authors: Oliver
authors: Marvin J
authors: MJ
authors: Miller
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: C540716:2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; D000995:Antitubercular Agents; D013141:Spiro Compounds; D013438:Sulfhydryl Compounds; D013843:Thiazines
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