Pretomanid | PA-824 | CAS#187235-37-6 | anti-tuberculosis drug

MedKoo Cat#: 206029 | Name: Pretomanid

Description:

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

Pretomanid, aslo known as PA-824, a bioreductive drug. PA-824 has potent in vitro activity against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC<1 microg/ml). PA-824 showed significant activity at 2, 10, and 50 microg/ml, similar to that of metronidazole, in a dose-dependent manner. PA-824's good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis.

Chemical Structure

Pretomanid

CAS#187235-37-6

Theoretical Analysis

MedKoo Cat#: 206029

Name: Pretomanid

CAS#: 187235-37-6

Chemical Formula: C14H12F3N3O5

Exact Mass: 359.0729

Molecular Weight: 359.26

Elemental Analysis: C, 46.80; H, 3.37; F, 15.86; N, 11.70; O, 22.27

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 650.00	Ready to ship
200mg	USD 950.00	Ready to ship
1g	USD 2,950.00	Ready to ship
2g	USD 4,850.00	Ready to ship

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Related CAS #

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Synonym

PA824; PA-824; PA 824; (S)-PA 824; Pretomanid.

IUPAC/Chemical Name

(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

InChi Key

ZLHZLMOSPGACSZ-NSHDSACASA-N

InChi Code

InChI=1S/C14H12F3N3O5/c15-14(16,17)25-10-3-1-9(2-4-10)7-23-11-5-19-6-12(20(21)22)18-13(19)24-8-11/h1-4,6,11H,5,7-8H2/t11-/m0/s1

SMILES Code

FC(F)(F)OC1=CC=C(C=C1)CO[C@H]2CN3C(OC2)=NC([N+]([O-])=O)=C3

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

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Pretomanid (PA-824) is an antibiotic used for the research of multi-drug-resistant tuberculosis affecting the lungs. Pretomanid exhibits a sub-micromolar MIC against M. tuberculosis (MTB).

In vitro activity:

In this context, pretomanid (PA-824), a novel nitroimidazole prodrug that targets both replicating and nonreplicating cells, is being developed by TB Alliance under license from Novartis. In replicating Mtb, pretomanid inhibits mycolic acid biosynthesis, which is an important building block of Mtb cell wall. Under nonreplicating conditions, pretomanid is reduced by deazaflavin-dependent nitroreductase, leading to generation of reactive nitrogen species exhibiting potent antimycobacterial activity. Reference: Drugs Today (Barc). 2020 Oct;56(10):655-668. https://pubmed.ncbi.nlm.nih.gov/33185630/

In vivo activity:

To better understand the relationship between drug exposure and effect, this study performed a dose fractionation study in mice. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Free drug T(>MIC) of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Reference: Antimicrob Agents Chemother. 2011 Jan;55(1):239-45. https://pubmed.ncbi.nlm.nih.gov/20937781/

	Solvent	mg/mL	mM
Solubility
	DMF	33.0	91.86
	DMSO	65.6	213.40
	DMSO:PBS (pH 7.2) (1:2)	0.3	0.92
	Ethanol	10.5	29.23

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 359.26 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. Thakare R, Dasgupta A, Chopra S. Pretomanid for the treatment of pulmonary tuberculosis. Drugs Today (Barc). 2020 Oct;56(10):655-668. doi: 10.1358/dot.2020.56.10.3161237. PMID: 33185630. 2. Patterson S, Wyllie S, Stojanovski L, Perry MR, Simeons FR, Norval S, Osuna-Cabello M, De Rycker M, Read KD, Fairlamb AH. The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral Leishmaniasis. Antimicrob Agents Chemother. 2013 Oct;57(10):4699-706. doi: 10.1128/AAC.00722-13. Epub 2013 Jul 15. PMID: 23856774; PMCID: PMC3811480. 3. Dutta NK, Karakousis PC. PA-824 is as effective as isoniazid against latent tuberculosis infection in C3HeB/FeJ mice. Int J Antimicrob Agents. 2014 Dec;44(6):564-6. doi: 10.1016/j.ijantimicag.2014.07.012. Epub 2014 Sep 16. PMID: 25270632; PMCID: PMC4256118. 4. Ahmad Z, Peloquin CA, Singh RP, Derendorf H, Tyagi S, Ginsberg A, Grosset JH, Nuermberger EL. PA-824 exhibits time-dependent activity in a murine model of tuberculosis. Antimicrob Agents Chemother. 2011 Jan;55(1):239-45. doi: 10.1128/AAC.00849-10. Epub 2010 Oct 11. PMID: 20937781; PMCID: PMC3019674.

In vitro protocol:

In vivo protocol:

1. Dutta NK, Karakousis PC. PA-824 is as effective as isoniazid against latent tuberculosis infection in C3HeB/FeJ mice. Int J Antimicrob Agents. 2014 Dec;44(6):564-6. doi: 10.1016/j.ijantimicag.2014.07.012. Epub 2014 Sep 16. PMID: 25270632; PMCID: PMC4256118. 2. Ahmad Z, Peloquin CA, Singh RP, Derendorf H, Tyagi S, Ginsberg A, Grosset JH, Nuermberger EL. PA-824 exhibits time-dependent activity in a murine model of tuberculosis. Antimicrob Agents Chemother. 2011 Jan;55(1):239-45. doi: 10.1128/AAC.00849-10. Epub 2010 Oct 11. PMID: 20937781; PMCID: PMC3019674.

1: McKenna L, Furin J. Are pretomanid-containing regimens for tuberculosis a victory or a victory narrative? Lancet Respir Med. 2019 Dec;7(12):999-1000. doi: 10.1016/S2213-2600(19)30363-7. Epub 2019 Nov 12. PubMed PMID: 31732486. 2: Tweed CD, Dawson R, Burger DA, Conradie A, Crook AM, Mendel CM, Conradie F, Diacon AH, Ntinginya NE, Everitt DE, Haraka F, Li M, van Niekerk CH, Okwera A, Rassool MS, Reither K, Sebe MA, Staples S, Variava E, Spigelman M. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med. 2019 Dec;7(12):1048-1058. doi: 10.1016/S2213-2600(19)30366-2. Epub 2019 Nov 12. PubMed PMID: 31732485. 3: Srivastava S, Deshpande D, Magombedze G, van Zyl J, Cirrincione K, Martin K, Bendet P, Berg A, Hanna D, Romero K, Hermann D, Gumbo T. Duration of pretomanid/moxifloxacin/pyrazinamide therapy compared with standard therapy based on time-to-extinction mathematics. J Antimicrob Chemother. 2019 Nov 12. pii: dkz460. doi: 10.1093/jac/dkz460. [Epub ahead of print] PubMed PMID: 31713607. 4: Keam SJ. Pretomanid: First Approval. Drugs. 2019 Nov;79(16):1797-1803. doi: 10.1007/s40265-019-01207-9. Review. PubMed PMID: 31583606. 5: Lyons MA. Modeling and Simulation of Pretomanid Pharmacodynamics in Pulmonary Tuberculosis Patients. Antimicrob Agents Chemother. 2019 Sep 30. pii: AAC.00732-19. doi: 10.1128/AAC.00732-19. [Epub ahead of print] PubMed PMID: 31570404; PubMed Central PMCID: PMC6879235. 6: Salinger DH, Subramoney V, Everitt D, Nedelman JR. Population Pharmacokinetics of the Antituberculosis Agent Pretomanid. Antimicrob Agents Chemother. 2019 Sep 23;63(10). pii: e00907-19. doi: 10.1128/AAC.00907-19. Print 2019 Oct. PubMed PMID: 31405856; PubMed Central PMCID: PMC6761531. 7: Li H, Salinger DH, Everitt D, Li M, Del Parigi A, Mendel C, Nedelman JR. Long-Term Effects on QT Prolongation of Pretomanid Alone and in Combinations in Patients with Tuberculosis. Antimicrob Agents Chemother. 2019 Sep 23;63(10). pii: e00445-19. doi: 10.1128/AAC.00445-19. Print 2019 Oct. PubMed PMID: 31358590; PubMed Central PMCID: PMC6761551. 8: Wen S, Jing W, Zhang T, Zong Z, Xue Y, Shang Y, Wang F, Huang H, Chu N, Pang Y. Comparison of in vitro activity of the nitroimidazoles delamanid and pretomanid against multidrug-resistant and extensively drug-resistant tuberculosis. Eur J Clin Microbiol Infect Dis. 2019 Jul;38(7):1293-1296. doi: 10.1007/s10096-019-03551-w. Epub 2019 Apr 5. PubMed PMID: 30953211. 9: Xu J, Li SY, Almeida DV, Tasneen R, Barnes-Boyle K, Converse PJ, Upton AM, Mdluli K, Fotouhi N, Nuermberger EL. Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis. Antimicrob Agents Chemother. 2019 Apr 25;63(5). pii: e00021-19. doi: 10.1128/AAC.00021-19. Print 2019 May. PubMed PMID: 30833432; PubMed Central PMCID: PMC6496099. 10: de Miranda Silva C, Hajihosseini A, Myrick J, Nole J, Louie A, Schmidt S, Drusano GL. Effect of Moxifloxacin plus Pretomanid against Mycobacterium tuberculosis in Log Phase, Acid Phase, and Nonreplicating-Persister Phase in an In Vitro Assay. Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: e01695-18. doi: 10.1128/AAC.01695-18. Print 2019 Jan. PubMed PMID: 30397058; PubMed Central PMCID: PMC6325209. 11: Shobo A, Pamreddy A, Kruger HG, Makatini MM, Naicker T, Govender T, Baijnath S. Enhanced brain penetration of pretomanid by intranasal administration of an oil-in-water nanoemulsion. Nanomedicine (Lond). 2018 May;13(9):997-1008. doi: 10.2217/nnm-2017-0365. Epub 2018 May 23. PubMed PMID: 29790418. 12: Lyons MA. Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients. Antimicrob Agents Chemother. 2018 Jun 26;62(7). pii: e02359-17. doi: 10.1128/AAC.02359-17. Print 2018 Jul. PubMed PMID: 29661865; PubMed Central PMCID: PMC6021621. 13: Baptista R, Fazakerley DM, Beckmann M, Baillie L, Mur LAJ. Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824). Sci Rep. 2018 Mar 23;8(1):5084. doi: 10.1038/s41598-018-23110-1. PubMed PMID: 29572459; PubMed Central PMCID: PMC5865180. 14: Thompson AM, Bonnet M, Lee HH, Franzblau SG, Wan B, Wong GS, Cooper CB, Denny WA. Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid. ACS Med Chem Lett. 2017 Nov 13;8(12):1275-1280. doi: 10.1021/acsmedchemlett.7b00356. eCollection 2017 Dec 14. PubMed PMID: 29259747; PubMed Central PMCID: PMC5733301. 15: Thompson AM, Marshall AJ, Maes L, Yarlett N, Bacchi CJ, Gaukel E, Wring SA, Launay D, Braillard S, Chatelain E, Mowbray CE, Denny WA. Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides. Bioorg Med Chem Lett. 2018 Jan 15;28(2):207-213. doi: 10.1016/j.bmcl.2017.10.067. Epub 2017 Oct 27. PubMed PMID: 29191556; PubMed Central PMCID: PMC5840523. 16: Li SY, Tasneen R, Tyagi S, Soni H, Converse PJ, Mdluli K, Nuermberger EL. Bactericidal and Sterilizing Activity of a Novel Regimen with Bedaquiline, Pretomanid, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis. Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: e00913-17. doi: 10.1128/AAC.00913-17. Print 2017 Sep. PubMed PMID: 28630203; PubMed Central PMCID: PMC5571308. 17: Momin MAM, Thien SJ, Krittaphol W, Das SC. Simultaneous HPLC assay for pretomanid (PA-824), moxifloxacin and pyrazinamide in an inhaler formulation for drug-resistant tuberculosis. J Pharm Biomed Anal. 2017 Feb 20;135:133-139. doi: 10.1016/j.jpba.2016.11.046. Epub 2016 Nov 25. PubMed PMID: 28024261. 18: Rakesh, Bruhn DF, Scherman MS, Singh AP, Yang L, Liu J, Lenaerts AJ, Lee RE. Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids. Bioorg Med Chem Lett. 2016 Jan 15;26(2):388-391. doi: 10.1016/j.bmcl.2015.12.002. Epub 2015 Dec 7. PubMed PMID: 26711150; PubMed Central PMCID: PMC4706794. 19: Tasneen R, Betoudji F, Tyagi S, Li SY, Williams K, Converse PJ, Dartois V, Yang T, Mendel CM, Mdluli KE, Nuermberger EL. Contribution of Oxazolidinones to the Efficacy of Novel Regimens Containing Bedaquiline and Pretomanid in a Mouse Model of Tuberculosis. Antimicrob Agents Chemother. 2015 Oct 26;60(1):270-7. doi: 10.1128/AAC.01691-15. Print 2016 Jan. PubMed PMID: 26503656; PubMed Central PMCID: PMC4704221. 20: López-Gavín A, Tudó G, Vergara A, Hurtado JC, Gonzalez-Martín J. In vitro activity against Mycobacterium tuberculosis of levofloxacin, moxifloxacin and UB-8902 in combination with clofazimine and pretomanid. Int J Antimicrob Agents. 2015 Nov;46(5):582-5. doi: 10.1016/j.ijantimicag.2015.08.004. Epub 2015 Sep 7. PubMed PMID: 26421981.