(S)-2-nitro-6-((6-(4-(trifluoroMethoxy)phenyl)pyridin-3-yl)Methoxy)-6,7-dihydro-5H-iMidazo[2,1-b][1,3]oxazine

Description

TBA-354 is a nitroimidazole antitubercular agent. It is active against clinical isolates of drug-resistant and -sensitive replicating M. tuberculosis (MICs = <0.02-0.36 μM). It is selective for M. tuberculosis over M. scrofulaceum, M. gilvum, M. fortuitum, M. triviale, and M. smegmatis (MICs = >11.5 μM) but is active against M. bovis and M. kansasii (MICs = <0.179 and 2.2 μM, respectively). TBA-354 (100 mg/kg per day) reduces lung colony forming units (CFUs) in mouse models of acute and chronic M. tuberculosis infection.

Uses

TBA-354 is a potent anti-tuberculosis compound; maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains. IC50 value: Target: Anti-tuberculosis agent in vitro: TBA-354 is narrow spectrum and bactericidal in vitro against replicating and nonreplicating Mycobacterium tuberculosis, with potency similar to that of delamanid and greater than that of PA-824. TBA-354 maintains activity against Mycobacterium tuberculosis H37Rv isogenic monoresistant strains and clinical drug-sensitive and drug-resistant isolates [1]. TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy [2]. in vivo: TBA-354 has high bioavailability and a long elimination half-life. In vitro studies suggest a low risk of drug-drug interactions. Low-dose aerosol infection models of acute and chronic murine tuberculosis reveal time- and dose-dependent in vivo bactericidal activity that is at least as potent as that of delamanid and more potent than that of PA-824.

References

[1]. upton am, cho s, yang tj, et al. in vitro and in vivo activities of the nitroimidazole tba-354 against mycobacterium tuberculosis. antimicrob agents chemother, 2015, 59(1): 136-144.
[2]. tasneen r, williams k, amoabeng o, et al. contribution of the nitroimidazoles pa-824 and tba-354 to the activity of novel regimens in murine models of tuberculosis. antimicrob agents chemother, 59 :129-135.