PBTZ169 | CAS#1377239-83-2 | DprE1 inhibitor

MedKoo Cat#: 522563 | Name: PBTZ169

Description:

WARNING: This product is for research use only, not for human or veterinary use.

PBTZ169, also known as macozinone, is a new drug candidate that inhibits decaprenyl-phosphoribose-epimerase (DprE1), an essential enzyme involved in the cell wall biosynthesis of Corynebacterineae. The MIC values of PBTZ169 ranged from 0.03 μg/mL to 0.0037 μg/mL. The MIC50 and MIC90 values of PBTZ169 were 0.0075 and 0.030 μg/mL, respectively. The MIC for PBTZ169 for N. brasiliensis HUJEG-1 was 0.0037 μg/mL. The MICs of SXT, DA-7218, and BTZ043 for this strain were 9.5/0.5, 8, and 0.125 μg/mL, respectively.

Chemical Structure

PBTZ169

CAS#1377239-83-2

Theoretical Analysis

MedKoo Cat#: 522563

Name: PBTZ169

CAS#: 1377239-83-2

Chemical Formula: C20H23F3N4O3S

Exact Mass: 456.1443

Molecular Weight: 456.48

Elemental Analysis: C, 52.62; H, 5.08; F, 12.49; N, 12.27; O, 10.51; S, 7.02

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,350.00	Ready to ship
500mg	USD 2,650.00	Ready to ship
1g	USD 3,850.00	Ready to ship
2g	USD 6,450.00	2 Weeks

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Related CAS #

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Synonym

PBTZ169; PBTZ-169; PBTZ 169; macozinone;

IUPAC/Chemical Name

2-(4-(cyclohexylmethyl)piperazin-1-yl)-8-nitro-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one

InChi Key

BJDZBXGJNBMCAV-UHFFFAOYSA-N

InChi Code

InChI=1S/C20H23F3N4O3S/c21-20(22,23)14-10-15-17(16(11-14)27(29)30)31-19(24-18(15)28)26-8-6-25(7-9-26)12-13-4-2-1-3-5-13/h10-11,13H,1-9,12H2

SMILES Code

O=C1N=C(N2CCN(CC3CCCCC3)CC2)SC4=C([N+]([O-])=O)C=C(C(F)(F)F)C=C14

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Note: 1. As of 1/6/2016, Sci-finder listed BTZ043 and PBTZ169 the same identity. It's CAS# was listed as 1161233-85-7 2. Our structure listed for BTZ043 was based on below publication, which has CAS# 1377239-83-2. Design, Syntheses, and Anti-TB Activity of 1,3-Benzothiazinone Azide and Click Chemistry Products Inspired by BTZ043 Rohit Tiwari, Patricia A. Miller, Laurent R. Chiarelli, Giorgia Mori, Michal Šarkan, Ivana Centárová, Sanghyun Cho, Katarína Mikušová, Scott G. Franzblau, llen G. Oliver, and Marvin J. Miller Publication Date (Web): January 4, 2016 (Letter) DOI: 10.1021/acsmedchemlett.5b00424

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A7K10C31

QC Data

View QC data: current batch, Lot#A7K10C31

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Macozinone (PBTZ169) is a bactericidal benzothiazinone and a potent DprE1 (decaprenylphosphoryl-β-d-ribose 2’-oxidase) inhibitor.

In vitro activity:

The most important finding of this study is that PBTZ169 exhibits excellent in vitro activity against MDR-TB and XDR-TB. All M. tuberculosis isolates tested have an MIC of less than 0.25 mg/liter, the MIC90 of which is significantly lower than those of moxifloxacin (16.0 mg/liter), linezolid (1.0 mg/liter), and clofazimine (1.0 mg/liter), while similar to those of bedaquiline (0.031 mg/liter) and delamanid (0.031 mg/liter) (18). Despite the limited data regarding plasma concentration of PBTZ169, the extremely low MICs against MDR-TB and XDR-TB highlight the promising efficacy of this anti-TB agent as part of a treatment for pulmonary MDR-TB and XDR-TB. Reference: Antimicrob Agents Chemother. 2018 Nov; 62(11): e01314-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201125/

In vivo activity:

Thus, the in vivo activity of these two drugs was evaluated in a mouse TB model (Fig. 2). At the concentrations tested, all drugs alone and in combinations significantly decreased the bacterial burden by more than 2.18 log10 in the lungs and 1.71 log10 in the spleens compared to the level on day 0, thus indicating a bactericidal effect. Although no combinatory effect was observed in these organs when MCZ (macozinone), DMD (delamanid), and STZ (sutezolid) were combined in two-drug combinations, the triple combination MCZ-DMD-STZ was more active in the lungs of M. tuberculosis-infected mice than DMD-STZ (the most active of the two-drug combinations) with bactericidal activity of more than 0.69 log10 CFU (P = 0.014). Reference: Antimicrob Agents Chemother. 2018 Nov; 62(11): e00840-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201121/

	Solvent	mg/mL	mM
Solubility
	DMSO	4.6	10.10

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 456.48 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Spaggiari D, Desfontaine V, Cruchon S, Guinchard S, Vocat A, Blattes E, Pitteloud J, Ciullini L, Bardinet C, Ivanyuk A, Makarov V, Ryabova O, Buclin T, Cole ST, Decosterd LA. Development and validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five active metabolites in human plasma. PLoS One. 2019 May 31;14(5):e0217139. doi: 10.1371/journal.pone.0217139. PMID: 31150423; PMCID: PMC6544242. 2. Shi J, Lu J, Wen S, Zong Z, Huo F, Luo J, Liang Q, Li Y, Huang H, Pang Y. In Vitro Activity of PBTZ169 against Multiple Mycobacterium Species. Antimicrob Agents Chemother. 2018 Oct 24;62(11):e01314-18. doi: 10.1128/AAC.01314-18. PMID: 30150479; PMCID: PMC6201125. 3. Lupien A, Vocat A, Foo CS, Blattes E, Gillon JY, Makarov V, Cole ST. Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169). Antimicrob Agents Chemother. 2018 Oct 24;62(11):e00840-18. doi: 10.1128/AAC.00840-18. PMID: 30126954; PMCID: PMC6201121. 4. González-Martínez NA, Lozano-Garza HG, Castro-Garza J, De Osio-Cortez A, Vargas-Villarreal J, Cavazos-Rocha N, Ocampo-Candiani J, Makarov V, Cole ST, Vera-Cabrera L. In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. PLoS Negl Trop Dis. 2015 Oct 16;9(10):e0004022. doi: 10.1371/journal.pntd.0004022. PMID: 26474057; PMCID: PMC4608729.

In vitro protocol:

In vivo protocol:

1. Lupien A, Vocat A, Foo CS, Blattes E, Gillon JY, Makarov V, Cole ST. Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169). Antimicrob Agents Chemother. 2018 Oct 24;62(11):e00840-18. doi: 10.1128/AAC.00840-18. PMID: 30126954; PMCID: PMC6201121. 2. González-Martínez NA, Lozano-Garza HG, Castro-Garza J, De Osio-Cortez A, Vargas-Villarreal J, Cavazos-Rocha N, Ocampo-Candiani J, Makarov V, Cole ST, Vera-Cabrera L. In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis. PLoS Negl Trop Dis. 2015 Oct 16;9(10):e0004022. doi: 10.1371/journal.pntd.0004022. PMID: 26474057; PMCID: PMC4608729.

1: Joshi T, Vijayakumar S, Ghosh S, Mathpal S, Ramaiah S, Anbarasu A. Identifying Novel Therapeutics for the Resistant Mutant "F533L" in PBP3 of Pseudomonas aeruginosa Using ML Techniques. ACS Omega. 2024 Jun 14;9(26):28046-28060. doi: 10.1021/acsomega.4c00929. PMID: 38973840; PMCID: PMC11223260. 2: Nikonenko B, Logunova N, Egorova A, Kapina M, Sterzhanova N, Bocharova I, Kondratieva E, Riabova O, Semyonova L, Makarov V; Dedicated to the 10th anniversary of the iM4TB Foundation. Efficacy of macozinone in mice with genetically diverse susceptibility to Mycobacterium tuberculosis infection. Microbes Infect. 2024 Jun 7:105376. doi: 10.1016/j.micinf.2024.105376. Epub ahead of print. PMID: 38852904. 3: Dube PS, Legoabe LJ, Jordaan A, Sigauke L, Warner DF, Beteck RM. Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling. Eur J Med Chem. 2023 Oct 5;258:115539. doi: 10.1016/j.ejmech.2023.115539. Epub 2023 Jun 9. PMID: 37321107. 4: Zheng L, Qi X, Zhang W, Wang H, Fu L, Wang B, Chen X, Chen X, Lu Y. Efficacy of PBTZ169 and pretomanid against Mycobacterium avium, Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum in BALB/c mice models. Front Cell Infect Microbiol. 2023 Mar 22;13:1115530. doi: 10.3389/fcimb.2023.1115530. PMID: 37077530; PMCID: PMC10106926. 5: Seidel RW, Richter A, Goddard R, Imming P. Synthesis, structures, reactivity and medicinal chemistry of antitubercular benzothiazinones. Chem Commun (Camb). 2023 Apr 18;59(32):4697-4715. doi: 10.1039/d3cc00356f. PMID: 36974371. 6: Desfontaine V, Guinchard S, Marques S, Vocat A, Moulfi F, Versace F, Huser- Pitteloud J, Ivanyuk A, Bardinet C, Makarov V, Ryabova O, André P, Prod'Hom S, Chtioui H, Buclin T, Cole ST, Decosterd L. Optimized LC-MS/MS quantification of tuberculosis drug candidate macozinone (PBTZ169), its dearomatized Meisenheimer Complex and other metabolites, in human plasma and urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Jan 15;1215:123555. doi: 10.1016/j.jchromb.2022.123555. Epub 2022 Dec 9. PMID: 36563654; PMCID: PMC9883661. 7: Imran M. Ethionamide and Prothionamide Based Coumarinyl-Thiazole Derivatives: Synthesis, Antitubercular Activity, Toxicity Investigations and Molecular Docking Studies. Pharm Chem J. 2022;56(9):1215-1225. doi: 10.1007/s11094-022-02782-0. Epub 2022 Dec 7. PMID: 36531826; PMCID: PMC9734486. 8: Koryakova A, Shcherbakova V, Riabova O, Kazaishvili Y, Bolgarin R, Makarov V. Antituberculosis Macozinone Extended-Release Tablets To Enhance Bioavailability: a Pilot Pharmacokinetic Study in Beagle Dogs. Microbiol Spectr. 2023 Feb 14;11(1):e0232722. doi: 10.1128/spectrum.02327-22. Epub 2022 Dec 12. PMID: 36507624; PMCID: PMC9927148. 9: Nguyen TQ, Hanh BTB, Jeon S, Heo BE, Park Y, Choudhary A, Moon C, Jang J. Synergistic Effect of Q203 Combined with PBTZ169 against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0044822. doi: 10.1128/aac.00448-22. Epub 2022 Nov 2. PMID: 36321819; PMCID: PMC9765072. 10: Imran M, Khan SA, Asdaq SMB, Almehmadi M, Abdulaziz O, Kamal M, Alshammari MK, Alsubaihi LI, Hussain KH, Alharbi AS, Alzahrani AK. An insight into the discovery, clinical studies, compositions, and patents of macozinone: A drug targeting the DprE1 enzyme of Mycobacterium tuberculosis. J Infect Public Health. 2022 Oct;15(10):1097-1107. doi: 10.1016/j.jiph.2022.08.016. Epub 2022 Sep 1. PMID: 36122509. 11: Poulton NC, Azadian ZA, DeJesus MA, Rock JM. Mutations in rv0678 Confer Low-Level Resistance to Benzothiazinone DprE1 Inhibitors in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0090422. doi: 10.1128/aac.00904-22. Epub 2022 Aug 3. PMID: 35920665; PMCID: PMC9487612. 12: Guo K, Shan Y, Zhang T, Li G, Li P, Ma C. Characterization of degradation products of Macozinone by LC-MS/MS and elucidation of their degradation pathway. J Pharm Biomed Anal. 2022 Sep 20;219:114865. doi: 10.1016/j.jpba.2022.114865. Epub 2022 Jun 2. PMID: 35716420. 13: Chen X, Li Y, Wang B, Lu Y. Identification of Mutations Associated With Macozinone-Resistant in Mycobacterium Tuberculosis. Curr Microbiol. 2022 May 26;79(7):205. doi: 10.1007/s00284-022-02881-x. PMID: 35616769. 14: Robertson GT, Ramey ME, Massoudi LM, Carter CL, Zimmerman M, Kaya F, Graham BG, Gruppo V, Hastings C, Woolhiser LK, Scott DWL, Asay BC, Eshun-Wilson F, Maidj E, Podell BK, Vásquez JJ, Lyons MA, Dartois V, Lenaerts AJ. Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 Inhibitors TBA-7371, PBTZ169, and OPC-167832. Antimicrob Agents Chemother. 2021 Oct 18;65(11):e0058321. doi: 10.1128/AAC.00583-21. Epub 2021 Aug 9. PMID: 34370580; PMCID: PMC8522729. 15: Khokhlov AL, Mariandyshev AO, Shcherbakova VS, Ozerova IV, Kazaishvili YG, Igumnova OV, Bolgarina AA, Rudoy BA. [Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе]. Ter Arkh. 2020 Dec 15;92(12):165-171. Russian. doi: 10.26442/00403660.2020.12.200482. PMID: 33720590. 16: Richter A, Goddard R, Schlegel T, Imming P, Seidel RW. 2-Chloro-3-nitro-5-(tri-fluoro-meth-yl)benzoic acid and -benzamide: structural characterization of two precursors for anti-tubercular benzo-thia-zinones. Acta Crystallogr E Crystallogr Commun. 2021 Jan 19;77(Pt 2):142-147. doi: 10.1107/S2056989021000517. PMID: 33614143; PMCID: PMC7869535. 17: Zhang G, Sheng L, Hegde P, Li Y, Aldrich CC. 8-cyanobenzothiazinone analogs with potent antitubercular activity. Med Chem Res. 2021;30(2):449-458. doi: 10.1007/s00044-020-02676-4. Epub 2021 Jan 13. PMID: 33462533; PMCID: PMC7805566. 18: Guo S, Fu L, Wang B, Chen X, Zhao J, Liu M, Lu Y. In vitro and in vivo antimicrobial activities of a novel piperazine-containing benzothiazinones candidate TZY-5-84 against Mycobacterium tuberculosis. Biomed Pharmacother. 2020 Nov;131:110777. doi: 10.1016/j.biopha.2020.110777. Epub 2020 Sep 25. PMID: 33152936. 19: Mariandyshev AO, Khokhlov AL, Smerdin SV, Shcherbakova VS, Igumnova OV, Ozerova IV, Bolgarina AA, Nikitina NA. [The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)]. Ter Arkh. 2020 Apr 27;92(3):61-72. Russian. doi: 10.26442/00403660.2020.03.000621. PMID: 32598795. 20: Wang A, Lv K, Tao Z, Gu J, Fu L, Liu M, Wan B, Franzblau SG, Ma C, Ma X, Han B, Wang A, Xu S, Lu Y. Identification of benzothiazinones containing an oxime functional moiety as new anti-tuberculosis agents. Eur J Med Chem. 2019 Nov 1;181:111595. doi: 10.1016/j.ejmech.2019.111595. 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