Carbon-14 radiolabeling andin vivobiodistribution of a potential anti-TB compound

Abstract

A potential anti-TB compound bearing a nitroimidazole moiety from iThemba Pharmaceuticals TB chemical library exhibits promising in vitro activity in the microplate almar blue assay (MABA) with a minimum inhibitory concentration (MIC) value of 3 µg/mL. It is equipotent to the front-line drug Isoniazid, but the compound is less toxic with an IC50 of >100 µg/mL. Therefore, this potential iThemba nitroimidazole, 4-([1,1'-[(14)C6]biphenyl]-4-ylmethyl)-9-nitro-3,4,5,6-tetrahydro-2H-imidazo[2,1-b][1,3,6]oxadiazocine, was radiolabeled with the C-14 isotope. The synthesis of the (14)C-labeled nitroimidazole was accomplished in seven steps from diethanolamine with a final specific radioactivity of 3.552 GBq/mmol, a radiochemical yield of 87%, and a radiochemical purity of ≥96%. The source of the C-14 radiolabel was bromobenzene which was introduced by the Suzuki-Miyaura reaction. Tissue distribution results showed that the radiotracer has a high accumulation in the lungs of TB-infected mice, statistically significantly higher than in healthy mice. However, the clearance (for both TB-infected and non-TB-infected mice) from all organs (except the small intestine) from 1 to 2 h as well as the low percentage of injected dose per gram values achieved indicates breakdown of the compound in vivo and subsequent clearance from the body. The latter suggests that the compound might not be useful as an anti-TB drug in humans.

Carbon‐14 radiolabelling and tissue distribution evaluation of a potential anti‐TB compound

“…This is gratifying as it indicates that the method followed is reliable although it indicates that the compound has no preference for TB in vivo . One would have expected higher lung uptake in the TB‐infected animals if the compound would have stayed intact in vivo . This is unexpected as the in vitro data suggest a higher MIC 99 value for this compound.…”

“…One would have expected higher lung uptake in the TB-infected animals if the compound would have stayed intact in vivo. 23 This is unexpected as the in vitro data suggest a higher MIC 99 value for this compound. The difference in vivo can possibly be explained by (1) that the compound is digested (broken down) in vivo and therefore only a part of the molecule (which no longer has anti-TB properties) is followed via the C-14 tracer or (2) the compound has no binding affinity for TB cells even if it has a high toxicity towards the cells.…”

Octahydro-1H,5H,7H-dipyrrolo[1,2-c:1′,2′-f][1,3,6]oxadiazocine-5-thione

“…The unsaturated benzoxadiazocine 8 was prepared as a novel heterocycle [8], and reaction of two equivalents of 2H-azirines with chlorosulfonyl isocyanate gives the oxadiazocinones 9 [9]. Various ring-fused derivatives are also known including the purine-fused compounds 10 [10], and the imidazo[2,1-b] fused compounds 11 which are active against tuberculosis and a range of other tropical diseases [11,12]. Compound 12 is formed as a byproduct in a Pictet Spengler reaction [13].…”

Accumulation of TB-Active Compounds in Murine Organs Relevant to Infection by Mycobacterium tuberculosis

“…It has already been shown that concentration of a particular drug in the lung for example may be higher than that in the plasma (Sonopo et al, 2015). Indeed, this trend is shown to obtain for the first-line TB drugs PZA, RIF, and INH whose concentrations in the lungs of uninfected primate species (baboons) were higher than in the plasma (Liu et al, 2010).…”