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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F19%3A73597162" target="_blank" >RIV/61989592:15310/19:73597162 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.9b00308" target="_blank" >https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.9b00308</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsmedchemlett.9b00308" target="_blank" >10.1021/acsmedchemlett.9b00308</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Medicinal Chemistry Letters

ISSN

1948-5875

e-ISSN

—

Svazek periodika

10

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

5

Strana od-do

1462-1466

Kód UT WoS článku

000490355900015

EID výsledku v databázi Scopus

2-s2.0-85072710278