Syntheses and Antituberculosis Activity of 1,3-Benzothiazinone Sulfoxide and Sulfone Derived from BTZ043

Abstract

The discovery of 1,3-benzothiazin-4-ones (BTZs), especially BTZ043 and PBTZ-169 as potent agents for the treatment of tuberculosis, prompted intensive research related to development of potential antituberculosis agents based on electron deficient nitroaromatic scaffolds. Herein we report the syntheses, computational and NMR studies and anti-TB activity of oxidation products, 1,3-benzothiazinone sulfoxide (BTZ-SO) and 1,3-benzothiazinone sulfone (BTZ-SO2) derived from BTZ043. The combined computational and NMR work revealed differences in the total charge densities and molecular shapes of the oxidation products. While docking studies still suggested similar interactions and binding patterns for both products with the target DprE1 enzyme, antituberculosis assays indicated remarkable differences in their activity. Interestingly, BTZ-SO possesses potent activity against nonpathogenic and pathogenic mycobacterial strains, but BTZ-SO2 is only weakly active.

Narrow-spectrum antibacterial agents

“…51, 52 BTZ043 exhibits high antimycobacterial selectivity, with no activity observed against representative Gram-positive ( S. aureus and Micrococcus luteus ) and Gram-negative ( P. aeruginosa and A. baumannii) strains. 53 Another class of DprE1 inhibitors is the 1,4-azaindole class, which unlike the benzothiazones, inhibit DprE1 via a non-covalent mechanism. The lead compounds from this series, 8 and 9 exhibit in vivo efficacy in both acute and chronic mouse TB models.…”

Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety

“…[2] <INSERT FIGURE 1 HERE> The structure-activity relationship (SAR) and mechanistic studies of BTZs suggest that the NO 2 group at position 8 and the sulfur atom at position 1 are critical for activity, that the -CF 3 at position 6 plays an important role in maintaining activity. [7,[13][14][15][16][17][18][19][20] In our previous study, we focused on the modification at position 2, some of the resulting compounds were found to have improved activity and pharmacokinetic properties. [11,12] Among them, IMB-ZR-1 with the piperidine ring displayed potent in vitro anti-TB activity against the tested MDR-TB strains (MIC = 0.016 µg/mL).…”

Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones

“…A series of potential DprE1 covalent inhibitors with modification on the 2 position of BTZs represented as compounds 1a and 2a was reported (Figure 1) [14][15][16][17]. Interestingly, two compounds with relatively minor modifications to the BTZs core, benzothiazinethione (SKLB-TB1001, 3) and sulfoxide of 1 (BTZ-SO, 4), maintain potent antimycobacterial activities (Figure 1) [18,19]. The crystal structures of the DprE1 with 1 and DprE1 with 2 complex as well as the structure-activity relationships (SARs) of this series indicated that the key constituents for potent activity are the sulfur atom and carbonyl group in the thiazinone ring, a strong electron withdrawing group (CF3, CN, NO2, etc.)…”