Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones.

Torres-Gómez H, Keiff F, Hortschansky P, Bernal F, Kerndl V, Meyer F, Messerschmidt N, Dal Molin M, Krüger T, Rybniker J, Brakhage AA, Kloss F (2024) Replacement of the essential nitro group by electrophilic warheads towards nitro-free antimycobacterial benzothiazinones. Eur J Med Chem 279, 116849.

Abstract

Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antitubercular drug candidates with two compounds in clinical phases. BTZs inhibit decaprenylphosphoryl-β-d-ribose oxidase 1 (DprE1), a key enzyme in cell wall biosynthesis of mycobacteria. Their mechanism of action involves an in-situ-reduction of the nitro moiety to a reactive nitroso intermediate capable of covalent binding to Cys387 in the catalytic cavity. The electron-deficient nature of the aromatic core is a key driver for the formation of hydride-Meisenheimer complexes (HMC) as main metabolites in vivo. To mimic the electrophilic character of the nitroso moiety, bioisosteric replacement with different electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for most active antimycobacterial compounds by enzymatic inhibition assays and peptide fragment analysis.

Leibniz-HKI-Autor*innen

Freddy Alexander Bernal
Axel A. Brakhage
Peter Hortschansky
François Keiff
Valerie Kerndl
Florian Kloß
Thomas Krüger
Nina Messerschmidt
Florian Meyer
Héctor Torres-Gomez

Identifier

doi: 10.1016/j.ejmech.2024.116849

PMID: 39265253