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

Abstract

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. Benzothiazinones (BTZs) are being developed as new antibiotics against the infection caused by Mycobacterium tuberculosis, however, BTZs can undergo an in vivo biotransformation to hydride-Meisenheimer complexes (HMC). Here, the authors show that HMC formation can be modulated by C-6 substitution of BTZ.