Deuterated antimicrobial compounds

US11731947B2 · kind B2 · utility

Assignee

• University of Notre Dame du Lac · US

Inventors

• Marvin J. Miller · South Bend, US
• Viktor Krchnak · San Diego, US
• Rui Liu · Cary, US

Key dates

• Filing date: Apr 3, 2020
• Grant date: Aug 22, 2023
• Expiry date: Jul 10, 2040

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C07D491/113
• WIPO field: Organic fine chemistry
• WIPO sector: Chemistry

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′-oxi-dase (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 NaBD4 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.