Whole cell hydride Meisenheimer complex biotransformation guided optimization of antimycobacterial benzothiazinones

Joch, Melanie; Wojtas, K. Philip; Torres-Gómez, Héctor; Li, Yan; Meyer, Florian; Straßburger, Maria; Kerndl, Valerie; Dahse, Hans-Martin; Hertweck, Christian; Hoffmann, Harald; Görls, Helmar; Walter, Kerstin; Hölscher, Christoph; Kloss, Florian

doi:10.1016/j.ejmech.2023.116023

Cited by 2 publications

(3 citation statements)

References 18 publications

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“…As the main goal of our work, we focused on the impact of C-6 substituents on the propensity to form HMC in our recently developed whole cell in vitro assay. Following our standardized protocol 15 , all measurements were normalized relative to BTZ-043 ( 1 ). Obtained HMC formation propensities (Table S5 ) were transformed into their negative decadic logarithm (pHMC) to ease data visualization and subsequent processing during chemoinformatics investigations (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The relevance of this metabolic pathway has also been confirmed in humans 13 , 14 , providing a strong rationale for lead optimization towards fast-follower candidates. Recently, we described the first robust in vitro HMC biotransformation assay based on a RAW cell line 15 . This assay enabled a first round of metabolism-guided lead optimization, in which we could demonstrate that substitution at positions C-5 and C-7 dramatically decreased HMC formation while the antitubercular activity could be retained for small substituents such as methyl and ethyl (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…This assay enabled a first round of metabolism-guided lead optimization, in which we could demonstrate that substitution at positions C-5 and C-7 dramatically decreased HMC formation while the antitubercular activity could be retained for small substituents such as methyl and ethyl (Fig. 2a ) 15 , 16 .

Fig.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of the Meisenheimer complex metabolism of nitro-benzothiazinones by targeted C-6 substitution

Keiff,

Bernal,

Joch

et al. 2024

Commun Chem

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Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health concern, demanding new antibiotics with innovative therapeutic principles due to the emergence of resistant strains. Benzothiazinones (BTZs) have been developed to address this problem. However, an unprecedented in vivo biotransformation of BTZs to hydride-Meisenheimer complexes has recently been discovered. Herein, we present a study of the influence of electron-withdrawing groups on the propensity of HMC formation in whole cells for a series of C-6-substituted BTZs obtained through reductive fluorocarbonylation as a late-stage functionalization key step. Gibbs free energy of reaction and Mulliken charges and Fukui indices on C-5 at quantum mechanics level were found as good indicators of in vitro HMC formation propensity. These results provide a first blueprint for the evaluation of HMC formation in drug development and set the stage for rational pharmacokinetic optimization of BTZs and similar drug candidates.

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Section: Resultsmentioning

confidence: 99%