Work

Deuteration of BTZ043 Extends the Lifetime of Meisenheimer Intermediates to the Antituberculosis Nitroso Oxidation State

Year: 2019

Type: article

Abstract: 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.

Source: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.9b00308

Authors: Rui Liu, Viktor Krchnak, Seth N. Brown, Marvin J. Miller

Institutions: University of Notre Dame, Palacký University Olomouc

Language: English

Topic: Phenothiazines and Benzothiazines Synthesis and Activities

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: University of Notre Dame, National Institute of Allergy and Infectious Diseases