PA-824

PA-824, a bicyclic nitroimidazoles, is an anti-tuberculosis (TB) agent that exerts potent in vitro activity against Mycobacterium tuberculosis with the minimal inhibition concentration (MIC) ranging from 0.015 μg/ml to 0.25 μg/ml and remains actively against a wide range of isolates that are resistant to commonly used anti-TB agents leading to its successful application in the treatment of TB [1].

PA-824 has been found to exhibit bactericidal activity against replicating bacilli and non-replicating bacilli under hypoxic or prolonged culture conditions in a dose dependent fashion through two possible mechanisms, which include PA-824 induced inhibition of ketomycolate synthesis and PA-824 mediated donation of nitric oxide during enzymatic nitro-reduction [1].

References:
[1] 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.

Pharmacokinetics and tissue distribution study of PA-824 in rats by LC-MS/MS.[Pubmed:26554313]

J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Dec 1;1006:194-200.

A simple, sensitive and rapid LC-MS/MS method has been developed and validated for determination of PA-824 in rat biological samples using darunavir as internal standard. Chromatographic separation was achieved on an Inertsil((R))ODS3 C18 column (150mmx4.6mm, 5mum) using gradient elution of methanol-0.1% ammonia in water (90:10, v/v) with fast gradient elution at a flow rate of 0.6mL/min and run time of 5min. The mass spectrometer was run in positive electrospray ionization (ESI) mode using multiple reaction monitoring (MRM) to monitor the mass transitions. The optimized ion transition pairs for quantitation were m/z360.1-->m/z175.0 for PA-824, m/z548.5-->m/z504.2 for IS. The method was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification (LLOQ), recovery, matrix effect and robustness. All validation parameters met the acceptance criteria according to regulatory guidelines. The LLOQ was 0.05mug/mL. The calibration curves showed a good linearity over the concentration range of 0.05-50mug/mL. The calibration curves for all biological samples showed good linearity (r(2)>0.9978) over the concentration ranges tested. The recoveries obtained for PA-824 were >/=88.8%. The developed method was successfully applied to investigate the pharmacokinetics and tissue distribution of PA-824 in rats following oral administration. It was also the first study to investigate the tissue distribution of PA-824 in rats following oral administration.

Synthesis and evaluation of pretomanid (PA-824) oxazolidinone hybrids.[Pubmed:26711150]

Bioorg Med Chem Lett. 2016 Jan 15;26(2):388-391.

Pretomanid (PA-824) is an important nitroimidazole antitubercular agent in late stage clinical trials. However, pretomanid is limited by poor solubility and high protein binding, which presents opportunities for improvement in its physiochemical properties. Conversely, the oxazolidinone linezolid has excellent physicochemical properties and has recently shown impressive activity for the treatment of drug resistant tuberculosis. In this study we explore if incorporation of the outer ring elements found in first and second generation oxazolidinones into the nitroimidazole core of pretomanid can be used to improve its physicochemical and antitubercular properties. The synthesis of pretomanid outer oxazolidinone ring hybrids was successfully performed producing hybrids that maintained antitubercular activity and had improved in vitro physicochemical properties. Three lead compounds were identified and evaluated in a chronic model of tuberculosis infection in mice. However, the compounds lacked efficacy suggesting that portions of PA-824 tail not found in the hybrid molecules are required for in vivo efficacy.

Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs.[Pubmed:26199118]

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3650-3.

Tuberculosis (TB) is a major global health problem, and new drug targets and scaffolds need to be identified to combat the emergence of drug resistant TB. The nitroimidazooxazine PA-824 represents a new class of bio-reductive drug to treat TB. In this study we report a 2-nitroimidazooxazine derivative with modification at the C-7 position that exhibited better activity than PA-824 against Mycobacterium tuberculosis (Mtb) H37Rv strain in vitro. From 7a as a key intermediate, we functionalized with benzyl ether (8), phenyl ether (9), benzyl carbonate (10) and benzyl carbamate (11). Among the 23 compounds produced, 8a-R (MIC=0.078 muM) with trifluoromethoxy benzyl group was 5-fold more potent than PA-824 (MIC=0.390 muM) in the in vitro assays against the wild-type Mtb, and the phenyl ether compound 9g-R (MIC=0.050 muM) exhibited the most potent antimycobacterial activity.

Simultaneous HPLC assay for pretomanid (PA-824), moxifloxacin and pyrazinamide in an inhaler formulation for drug-resistant tuberculosis.[Pubmed:28024261]

J Pharm Biomed Anal. 2017 Feb 20;135:133-139.

A simple and sensitive reversed phase HPLC method has been developed for the simultaneous quantitation of pretomanid (PA-824), moxifloxacin and pyrazinamide in a combination spray-dried powder formulation for inhalation, without any use of an internal standard. Good resolution of the analytes was achieved on a Luna C18 (2), 150x4.6mm, 5mum, 100A column using gradient elution with a mobile phase containing methanol and triethylamine phosphate buffer (pH 2.5) at a flow rate of 1.0mL/min in a total run time of 25min. Pyrazinamide, moxifloxacin and pretomanid (PA-824) were detected at wavelengths (retention times) of 269nm (3.80min), 296nm (7.94min) and 330nm (17.46min), respectively. The assay was linear for all analytes in the concentration range 2.5-100mug/mL (correlation coefficients >0.999) with LODs and LLOQs (mug/mL) of pretomanid (PA-824) 0.51 and 1.56, moxifloxacin 0.06 and 0.19 and pyrazinamide 0.35 and 1.06, respectively. Recoveries of the three drugs were 99.6-106.8% with intra- and inter-day precisions (as relative standard deviation) of <7%. The method was successfully applied to an evaluation of content uniformity and freedom from interference by l-leucine of a spray-dried combination powder for inhalation.

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). The MIC values of PA-824 against a panel of MTB pan-sensitive and Rifampin mono-resistant clinical isolates range from 0.015 to 0.25 µg/mL.

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