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Purity: ≥98%
BTZ043 racemate, the racemic mixture (R- and S-isomer) of BTZ043, is a decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) inhibitor acting as a new antimycobacterial agent that kill Mycobacterium tuberculosis. BTZ043 displayed similar activity against all clinical isolates of M. tuberculosis that were tested, including extensively drug-resistant and multidrug-resistant strains, indicating that it targets a previously unknown biological function. BTZ043 is bactericidal, reducing viability in vitro by more than 1000-fold in under 72 hours, which is comparable to the INH killing effect. It has potential to be used as a antimycobacterial agent that kill Mycobacterium tuberculosis by blocking arabinan synthesis. The inhibition of BTZ-resistant DprE1 followed the trend observed in the MIC measurements, with the C387G mutant being more resistant to inhibition by PyrBTZ01, PyrBTZ02, and BTZ043 (7- to 9-fold increases in IC50) than the C387S mutant (2.5- to 4-fold increases in IC50). Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. BTZ043 presented favorable in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. BTZ043 did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.
| Targets |
DprE1
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| ln Vitro |
By targeting decaprenylphosphoryl-β-D-ribose 2-epimerase, BTZ043 abolishes the formation of decaprenylphosphoryl arabinose, leading to cell lysis and death of Mycobacterium tuberculosis. BTZ043 displays similar activity against all clinical isolates of M. tuberculosis, including multidrug-resistant and extensively drug-resistant strains. BTZ043 displays significant activity against M. tuberculosis H37Rv and Mycobacterium smegmatis with MIC of 1 ng/mL (2.3 nM) and 4 ng/mL (9.2 nM), respectively, which is more potent than those of the existing tuberculosis (TB) drugs isoniazid (INH) and ethambutol (EMB) with MIC of 0.02-0.2 μg/mL and 1-5 μg/mL, respectively. BTZ043 is less effective in two different model systems (auxotrophy and starvation) involving metabolically inert M. tuberculosis, indicating that BTZ043 blocks a step in active metabolism similar to isoniazid (INH). BTZ043 treatment in M. smegmatis cells decreases the growth rate rapidly followed by a swelling of the poles and lysis of the cells after a few hours, which is similar but delayed in M. tuberculosis. BTZ043 (1/4 MIC 0.375 ng/mL) in combination with TMC207 (1/4 MIC 20 ng/mL) has a stronger cidal effect on M. tuberculosis but not BTZ-resistant M. tuberculosis mutant than TMC207 alone at a concentration of 80 ng/mL.
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| ln Vivo |
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| Enzyme Assay |
BTZ043, also known as 8-Nitro-benzothiazinones (BTZs), is a potent inhibitor of decaprenyl-phosphoribose-epimerase (DprE1) with MIC values of of 2.3 nM and 9.2 nM for M. tuberculosis H37Rv and Mycobacterium smegmatis, respectively.
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| Cell Assay |
BTZ043 displayed similar activity against all clinical isolates of M. tuberculosis that were tested, including extensively drug-resistant and multidrug-resistant strains, indicating that it targets a previously unknown biological function. BTZ043 is bactericidal, reducing viability in vitro by more than 1000-fold in under 72 hours, which is comparable to the INH killing effect.
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| References |
| Molecular Formula |
C17H16F3N3O5S
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| Molecular Weight |
431.38
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| Exact Mass |
431.08
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| Elemental Analysis |
C, 47.33; H, 3.74; F, 13.21; N, 9.74; O, 18.54; S, 7.43
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| CAS # |
957217-65-1
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| Related CAS # |
BTZ043;1161233-85-7
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| Appearance |
Solid powder
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| SMILES |
O=C1N=C(N(CC2)CCC32OCC(C)O3)SC4=C([N+]([O-])=O)C=C(C(F)(F)F)C=C14
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| InChi Key |
GTUIRORNXIOHQR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H16F3N3O5S/c1-9-8-27-16(28-9)2-4-22(5-3-16)15-21-14(24)11-6-10(17(18,19)20)7-12(23(25)26)13(11)29-15/h6-7,9H,2-5,8H2,1H3
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| Chemical Name |
2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-8-nitro-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 22~25 mg/mL ( 50.99~57.95 mM )
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.80 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.38 mg/mL (3.20 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 13.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: 2.5 mg/mL (5.80 mM) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3181 mL | 11.5907 mL | 23.1814 mL | |
| 5 mM | 0.4636 mL | 2.3181 mL | 4.6363 mL | |
| 10 mM | 0.2318 mL | 1.1591 mL | 2.3181 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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Comparative BTZ efficacy in in vitro, ex vivo, and mouse models.Science.2009 May 8;324(5928):801-4. |
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Inhibition of decaprenylphosphoryl-β-d-ribose epimerization by BTZ.Science.2009 May 8;324(5928):801-4. |
 Identification of the BTZ target.Science.2009 May 8;324(5928):801-4. |
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