PA-824

• CAT Number: I002421
• CAS Number: 187235-37-6
• Molecular Formula: C14H12F3N3O5
• Purity: ≥95%
• Target: tuberculosis
• Solubility: DMSO: ≥ 34 mg/mL
• Storage: 3 years -20C powder
• IC50: 0.015 to 0.25 ug/ml (MICs) [1]
• InChI: 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
• InChIKey: ZLHZLMOSPGACSZ-NSHDSACASA-N
• SMILES: FC(F)(F)OC1=CC=C(CO[C@@H]2COC3=NC([N+]([O-])=O)=CN3C2)C=C1

PA-824(Pretomanid) is a small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis; the MIC values of PA-824 against a panel of MTB pan-sensitive and rifampin mono-resistant clinical isolates ranged from 0.015 to 0.25 ug/ml.IC50 value: 0.015 to 0.25 ug/ml (MICs) [1]Target: tuberculosisPA-824 exhibited a sub-micromolar minimal inhibitory concentration (MIC) against MTB, Although PA-824 was not the most potent NAP against cultured MTB clinical isolates, it was the most active in infected mice when orally administered at 25 mg kg -1. This indicated that PA-824 might possess more desirable pharmacokinetic properties than the other more potent NAP compounds that we tested. Further studies in mice at 25, 50 and 100 mg kg-1 PA-824 daily for 10 days resulted in reductions of mycobacterial burden in both spleen and lung tissues that were comparable to that of INH at 25 mg kg -1 [1]. PA-824 showed significant activity at 2, 10, and 50 microg/ml, similar to that of metronidazole, in a dose-dependent manner. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen [2]. PA-824 has no effect on the viability of M. leprae in all three models, consistent with the lack of the nitroimidazo-oxazine-specific nitroreductase, encoded by Rv3547 in the M. leprae genome, which is essential for activation of this molecule [3].

Reference

1:Simultaneous HPLC assay for pretomanid (PA-824), moxifloxacin and pyrazinamide in an inhaler formulation for drug-resistant tuberculosis. Momin MA, Thien SJ, Krittaphol W, Das SC.J Pharm Biomed Anal. 2017 Feb 20;135:133-139. doi: 10.1016/j.jpba.2016.11.046. Epub 2016 Nov 25. PMID: 28024261 2:Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids. Rakesh, Bruhn DF, Scherman MS, Singh AP, Yang L, Liu J, Lenaerts AJ, Lee RE.Bioorg Med Chem Lett. 2016 Jan 15;26(2):388-91. doi: 10.1016/j.bmcl.2015.12.002. Epub 2015 Dec 7. PMID: 26711150 Free PMC Article3:Pharmacokinetics and tissue distribution study of PA-824 in rats by LC-MS/MS. Wang L, Ma Y, Duan H, Yao J, Liang L, Zhang R, Zhou X, Liu X, Wang Q, Zhang S.J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Dec 1;1006:194-200. doi: 10.1016/j.jchromb.2015.10.039. Epub 2015 Oct 29. PMID: 26554313 4:Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs. Kang YG, Park CY, Shin H, Singh R, Arora G, Yu CM, Lee IY.Bioorg Med Chem Lett. 2015 Sep 1;25(17):3650-3. doi: 10.1016/j.bmcl.2015.06.060. Epub 2015 Jul 2. PMID: 26199118 5:Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of Mycobacterium tuberculosis. Haver HL, Chua A, Ghode P, Lakshminarayana SB, Singhal A, Mathema B, Wintjens R, Bifani P.Antimicrob Agents Chemother. 2015 Sep;59(9):5316-23. doi: 10.1128/AAC.00308-15. Epub 2015 Jun 22. PMID: 26100695 Free PMC Article6:Structural insights of PA-824 derivatives: ligand-based 3D-QSAR study and design of novel PA824 derivatives as anti-tubercular agents. Inturi B, Pujar GV, Purohit MN.J Recept Signal Transduct Res. 2015;35(5):468-78. doi: 10.3109/10799893.2015.1015734. Epub 2015 Jun 8. PMID: 26053507 7:Determination of the antitubercular drug PA-824 in rat plasma, lung and brain tissues by liquid chromatography tandem mass spectrometry: application to a pharmacokinetic study. Bratkowska D, Shobo A, Singh S, A Bester L, Kruger HG, Maguire GE, Govender T.J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Apr 15;988:187-94. doi: 10.1016/j.jchromb.2015.02.041. Epub 2015 Mar 9. PMID: 25796075 8:Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA, Schall R, Spigelman M, Conradie A, Eisenach K, Venter A, Ive P, Page-Shipp L, Variava E, Reither K, Ntinginya NE, Pym A, von Groote-Bidlingmaier F, Mendel CM.Lancet. 2015 May 2;385(9979):1738-47. doi: 10.1016/S0140-6736(14)62002-X. Epub 2015 Mar 18. PMID: 25795076 9:Synthesis and structure-activity relationships for extended side chain analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824). Palmer BD, Sutherland HS, Blaser A, Kmentova I, Franzblau SG, Wan B, Wang Y, Ma Z, Denny WA, Thompson AM.J Med Chem. 2015 Apr 9;58(7):3036-59. doi: 10.1021/jm501608q. Epub 2015 Mar 27. PMID: 25781074 10:Contribution of the nitroimidazoles PA-824 and TBA-354 to the activity of novel regimens in murine models of tuberculosis. Tasneen R, Williams K, Amoabeng O, Minkowski A, Mdluli KE, Upton AM, Nuermberger EL.Antimicrob Agents Chemother. 2015 Jan;59(1):129-35. doi: 10.1128/AAC.03822-14. Epub 2014 Oct 20. PMID: 25331697 Free PMC Article