BTZ-Derived Benzisothiazolinones with In Vitro Activity against <i>Mycobacterium tuberculosis</i>

8-Nitro-1,3-benzothiazin-4-ones (BTZs) are known as potent
antitubercular
agents. BTZ043 as one of the most advanced compounds has reached clinical
trials. The putative oxidation products of BTZ043, namely, the corresponding
BTZ sulfoxide and sulfone, were reported in this journal (Tiwari et
al. ACS Med. Chem Lett. 2015, 6, 128–133). The molecular structures were later
revised to the constitutionally isomeric benzisothiazolone and its
1-oxide, respectively. Here, we report two BTZ043-derived benzisothiazolinones
(BITs) with in vitro activity against mycobacteria. The constitutionally
isomeric O-acyl benzisothiazol-3-ols, in contrast,
show little or no antimycobacterial activity in vitro. The structures
of the four compounds were investigated by X-ray crystallography and
NMR spectroscopy. Molecular covalent docking of the new compounds
to Mycobacerium tuberculosis decaprenylphosphoryl-β-d-ribose
2′-epimerase (DprE1) suggests that the active BITs exert antimycobacterial
activity through inhibition of DprE1 like BTZs.