New Insight into Dearomatization and Decarbonylation of Antitubercular 4H-Benzo[e][1,3]thiazinones: Stable 5H- and 7H-Benzo[e][1,3]thiazines

Abstract

8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds' antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH₃ MgBr afford the corresponding dearomatized stable 4,5-dimethyl-5H- and 4,7-dimethyl-7H-benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X-ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non-planar 4H-benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH₃ )₂ S ⋅ BH₃ . Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays.

Keywords: BTZ043; DprE1 inhibitors; benzothiazines; benzothiazinones; tuberculosis.

Scheme 1

Chemical diagrams of the antitubercular BTZs 1 a and 1 b (BTZ043).

Scheme 2

Reaction products after treatment of BTZs 1 a and 1 b with the Grignard reagent CH₃MgBr, subsequent hydrolysis and dehydration (3 and 5) or air oxidation (7 and 9). Compounds 2, 4, 6 and 8 were not isolated.

Figure 1

¹H NMR spectra (400 MHz, CDCl₃) of the 5H‐ and 7H‐benzo[e][1,3]thiazines 3 a and 5 a, the monomethyl BTZs 7 a and 9 a and the parent BTZ 1 a. S denotes the residual solvent signal.

Figure 2

Molecular structures of 3 a (top) and 5 a (bottom) in the crystal, showing the R enantiomer in both cases. Displacement ellipsoids are drawn at the 50 % probability level. Hydrogen atoms are represented by small spheres of arbitrary radius. The minor part of the rotationally disordered trifluoromethyl group (ca. 3 %) in 5 a is omitted clarity (see Figure S3 in the Supporting Information). Colour scheme: C grey, H white, N blue, O red, S yellow.

Figure 3

Part of the asymmetric unit of 3 b. Displacement ellipsoids are drawn at the 50 % probability level. Hydrogen atoms are represented by small spheres of arbitrary radius. For the sake of clarity only unique molecules 1 and 2 (as indicated by the number after the underscore) are depicted (for molecules 3 and 4, see Supporting information). Colour scheme: C grey, H white, N blue, O red, S yellow.

Figure 4

Displacement ellipsoid plot of 7 b (50 % probability level). Hydrogen atoms are represented by small spheres of arbitrary radius. The number after the underscore indicates the crystallographically unique molecules 1 and 2. Colour scheme: C grey, H white, N blue, O red, S yellow.

Scheme 3

Reaction products after treatment of BTZs 1 a and 1 b with the reducing agent (CH₃)₂S ⋅ BH₃ and subsequent hydrolysis.

Figure 5

Molecular structure of 10 a in the crystal. Displacement ellipsoids are drawn at the 50 % probability level. Hydrogen atoms are represented by small spheres of arbitrary radius. Colour scheme: C grey, H white, N blue, O red, S yellow.