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BTZ043 Sale

(Synonyms: 2-[(2S)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基]-8-硝基-6-三氟甲基-4H-1,3-苯并噻嗪-4-酮) 目录号 : GC40680

An antibiotic with antimycobacterial activity

BTZ043 Chemical Structure

Cas No.:1161233-85-7

规格 价格 库存 购买数量
1mg
¥411.00
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5mg
¥1,122.00
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10mg
¥1,887.00
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25mg
¥5,667.00
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实验参考方法

Animal experiment:

Mice[2]Animal efficacy is determined in a standard mouse infection model. BALB/c mice are infected with a low bacillary load (~200 CFU) of M. tuberculosis H37Rv via aerosol. Treatment started four-weeks post infection. Mice are dosed by gavage with 37.5, or 300 mg of BTZ043, per kg body weight, in carboxymethyl cellulose formulation (0.25%), once daily, six times/week, for four weeks. Control and treated mice are sacrificed, lungs and spleens homogenized and dilutions plated for enumeration of viable bacilli[2].

References:

[1]. Vadim Makarov et al. The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 fromMycobacterium tuberculosis. Antimicrob Agents Chemother, 2015 Aug, 59(8): 4446-4452.
[2]. Makarov V, et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science. 2009 May 8;324(5928):801-4.
[3]. Norma Alejandra González-Martínez et al. In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. PLoS Negl Trop Dis, 2015 Oct, 9(10): e0004022.

产品描述

BTZ043 is an inhibitor of decaprenyl-phosphoribose-epimerase (DprE1), with MICs of of 2.3 nM and 9.2 nM for M. tuberculosis H37Rv and Mycobacterium smegmatis, respectively.

The MIC of BTZ043 against M. tuberculosis H37Rv and Mycobacterium smegmatis are 1 ng/mL (2.3 nM) and 4 ng/mL (9.2 nM), respectively[2]. The in vitro activity of BTZ043 against 30 Nocardia brasiliensis isolates is also tested. The MIC50 and MIC90 values for BTZ043 are 0.125 and 0.25 μg/mL. The MIC for N. carnea ATCC 6847 is 0.003μg/mL, for N. transvalensis ATCC 6865 is 0.003μg/mL, for N. brasiliensis NCTC10300 is 0.03 μg/mL, and for N. brasiliensis HUJEG-1 is 0.125μg/mL. The MIC value for M. tuberculosis H37Rv is 0.000976 μg/mL. The MIC value of BTZ-043 is >64 μg/mL for Escherichia coli ATCC 25922 and S. aureus ATCC 29213[3].

Four weeks of treatment with BTZ043 reduces the bacterial burden in the lungs and spleens by 1 and 2 logs, respectively, at the concentrations used. Additional results suggest that BTZ043 efficacy is time-rather than dose-dependent. Acute (5 g/kg) and chronic (25 and 250 mg/kg) toxicology studies in uninfected mice show that, even at the highest dose tested, there are no adverse anatomical, behavioral, or physiological effects after one month[2].

References:
[1]. Vadim Makarov et al. The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 fromMycobacterium tuberculosis. Antimicrob Agents Chemother, 2015 Aug, 59(8): 4446-4452.
[2]. Makarov V, et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science. 2009 May 8;324(5928):801-4.
[3]. Norma Alejandra González-Martínez et al. In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. PLoS Negl Trop Dis, 2015 Oct, 9(10): e0004022.

Chemical Properties

Cas No. 1161233-85-7 SDF
别名 2-[(2S)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基]-8-硝基-6-三氟甲基-4H-1,3-苯并噻嗪-4-酮
Canonical SMILES O=C1N=C(N2CCC3(OC[C@H](C)O3)CC2)SC4=C([N+]([O-])=O)C=C(C(F)(F)F)C=C41
分子式 C17H16F3N3O5S 分子量 431.4
溶解度 DMF: 1 mg/ml,DMSO: 1 mg/ml 储存条件 Store at -20°C
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溶解性数据

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1 mg 5 mg 10 mg
1 mM 2.318 mL 11.5902 mL 23.1803 mL
5 mM 0.4636 mL 2.318 mL 4.6361 mL
10 mM 0.2318 mL 1.159 mL 2.318 mL
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Research Update

Deuteration of BTZ043 Extends the Lifetime of Meisenheimer Intermediates to the Antituberculosis Nitroso Oxidation State

ACS Med Chem Lett 2019 Aug 29;10(10):1462-1466.PMID:31620234DOI:10.1021/acsmedchemlett.9b00308.

Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphosphoryl-β-d-ribose-2'-oxidase (DprE1) of Mycobacterium tuberculosis (Mtb). The resulting cell wall synthesis inhibition is lethal to Mtb, leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex. Herein we demonstrate that chemical reduction of BTZ043 with NaBD4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.

Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043

ACS Med Chem Lett 2016 Jan 4;7(3):266-70.PMID:26985313DOI:10.1021/acsmedchemlett.5b00424.

Electron deficient nitroaromatic compounds such as BTZ043 and its closest congener, PBTZ169, and related agents are a promising new class of anti-TB compounds. Herein we report the design and syntheses of 1,3-benzothiazinone azide (BTZ-N3) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N3 binds in the essentially same pocket as that of BTZ043. Detailed biochemical studies with cell envelope enzyme fractions of Mycobacterium smegmatis combined with our model biochemical reactivity studies with nucleophiles indicated that, in contrast to BTZ043, the azide analogue may have a different mode of activation for anti-TB activity. Subsequent enzymatic studies with recombinant DprE1 from Mtb followed by MIC determination in NTB1 strain of Mtb (harboring Cys387Ser mutation in DprE1 and is BTZ043 resistant) unequivocally indicated that BTZ-N3 is an effective reversible and noncovalent inhibitor of DprE1.

In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis

Antimicrob Agents Chemother 2012 Nov;56(11):5790-3.PMID:22926573DOI:10.1128/AAC.01476-12.

Benzothiazinones (BTZ) are a new class of drug candidates to combat tuberculosis that inhibit decaprenyl-phosphoribose epimerase (DprE1), an essential enzyme involved in arabinan biosynthesis. Using the checkerboard method and cell viability assays, we have studied the interaction profiles of BTZ043, the current lead compound, with several antituberculosis drugs or drug candidates against Mycobacterium tuberculosis strain H37Rv, namely, rifampin, isoniazid, ethambutol, TMC207, PA-824, moxifloxacin, meropenem with or without clavulanate, and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. Data from two different approaches clearly indicate that BTZ043 acts synergistically with TMC207, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng/ml) used in combination with BTZ043 (1/4 MIC, 0.375 ng/ml) had a stronger bactericidal effect on M. tuberculosis than TMC207 alone at a concentration of 80 ng/ml. This synergy was not observed when the combination was tested on a BTZ-resistant M. tuberculosis mutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. We therefore hypothesize that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of TMC207 to its target. Synergy between two new antimycobacterial compounds, such as TMC207 and BTZ043, with novel targets, offers an attractive foundation for a new tuberculosis regimen.

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

ACS Med Chem Lett 2014 Nov 29;6(2):128-33.PMID:25699139DOI:10.1021/ml5003458.

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.

In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation

Angew Chem Int Ed Engl 2017 Feb 13;56(8):2187-2191.PMID:28097740DOI:10.1002/anie.201609737.

Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.