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

ABSTRACT: Nitrobenzothiazinones (BTZs) are undergoing late-stage development as a novel class of potent antituberculotic 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 against electrophilic warheads was attempted to reduce HMC formation without compromising covalent reactivity. Herein, we synthesized and characterized a set of various covalent warheads covering different reaction principles. Covalent inhibition was confirmed for all antimycobacterial compounds by enzymatic inhibition assays and protein mass spectrometry analysis.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mycobacterium Tuberculosis Kt-0001

SUBMITTER: Thomas Krüger

LAB HEAD: Axel A. Brakhage

PROVIDER: PXD053165 | Pride | 2024-09-11

REPOSITORIES: Pride

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			Action	DRS
	DprE1_DMSO-a.raw	Raw
	DprE1_DMSO-b.raw	Raw
	DprE1_DMSO-c.raw	Raw
	DprE1_DMSO.fasta	Fasta
	DprE1_DMSO.mgf	Mgf

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