Open AccessDeuteration of BTZ043 Extends the Lifetime of Meisenheimer Intermediates to the Antituberculosis Nitroso Oxidation State
Author(s) -
Rui Li,
Viktor Krchňák,
Seth N. Brown,
Marvin J. Miller
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00308
Subject(s) - chemistry , nitroso , adduct , deuterium , cysteine , cysteamine , nitro , ribose , prodrug , nitroso compounds , oxidation state , combinatorial chemistry , stereochemistry , medicinal chemistry , alkyl , organic chemistry , enzyme , biochemistry , metal , physics , quantum mechanics
Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphosphoryl-β-d-ribose-2'-oxidase (DprE1) of Mycobacterium tuberculosis ( Mtb ). The resulting cell wall synthesis inhibition is lethal to Mtb , leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex. Herein we demonstrate that chemical reduction of BTZ043 with NaBD 4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.