Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones

Balungile Madikizela,Tamira Eckhardt,Rüdiger W Seidel,Christoph Lehmann,Peter Imming,Anika Lins,Richard Goddard,Adrian Richter

doi:10.1007/s00044-021-02735-4

Abstract

8-Nitro-1,3-benzothiazin-4-ones (BTZs), with BTZ043 and PBTZ169 as the most advanced compounds, represent a new class of potent antitubercular agents, which irreversibly inhibit decaprenylphosphoryl-β-d-ribose-2′-epimerase (DprE1), an enzyme crucial for cell wall synthesis in the pathogen Mycobacterium tuberculosis. Synthesis, structural characterization and in vitro testing against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv of halogenated 2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-ones lacking a nitro group are reported. X-ray crystallography reveals that the structure of the BTZ scaffold can significantly deviate from planarity. In contrast to recent reports, the results of the present study indicate that further investigation of halogenated non-nitro BTZs for antitubercular activity is less than a promising approach.

Highlights

Tuberculosis (TB) is an infectious disease, which is among the top ten causes of death worldwide
Nosova et al published a series of fluorinated BTZs lacking a nitro group, for one of which, namely 5-fluoro2-(4-ethoxycarbonylpiperazine-1-yl)-1,3-benzothiazin-4-one, a promising in vitro activity against M. tuberculosis H37Rv of 0.7 μg mL−1 (2 μM) was reported [21, 22]
We synthesized and structurally characterized the aforementioned most active compound described by Nosova et al and four related halogenated non-nitro BTZs and tested their in vitro activities against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv

Summary

Introduction

Tuberculosis (TB) is an infectious disease, which is among the top ten causes of death worldwide. Nosova et al published a series of fluorinated BTZs lacking a nitro group, for one of which, namely 5-fluoro2-(4-ethoxycarbonylpiperazine-1-yl)-1,3-benzothiazin-4-one, a promising in vitro activity against M. tuberculosis H37Rv of 0.7 μg mL−1 (2 μM) was reported [21, 22]. Motivated by these findings, we synthesized and structurally characterized the aforementioned most active compound described by Nosova et al and four related halogenated non-nitro BTZs and tested their in vitro activities against Mycobacterium aurum DSM 43999 and M. tuberculosis H37Rv. M. aurum, a fast-growing mycobacterial species with low pathogenicity [23], is considered a good model for M. tuberculosis [24, 25]. Compounds 2a-e were characterized by 1H and 13C NMR spectroscopy and highresolution mass spectrometry (see Supplementary Material)

Results and discussion

Conclusions

Compliance with ethical standards