(+)-Oxo-tomaymycin,
a naturally occurring substance of the pyrrolo-1,4-benzodiazepine
family, was synthesized using a short and efficient route. The key
construction of the seven-membered ring by amide bond formation was
realized via a chemoselective Ar-NO2 reduction using TiCl3 under acidic conditions, followed by a spontaneous cyclization.
This synthesis was easily scaled up to 80 g, and it should be amenable
to the production of larger quantities.
A series of 2(5H)-furanone-based compounds were synthesized from commercially available mucohalic acids. From the first-generation compounds, three showed inhibitory activity (10 mg/mL) of at least 35% against Mycobacterium smegmatis mc 2 155 growth (Bioscreen C system). In screening the active first-generation compounds for growth inhibition against Mycobacterium tuberculosis H37Rv, the most active compound was identified with a minimum inhibitory concentration (MIC 99 ) of 8.07 mg/mL (15.8 mM) using BACTEC 460 system. No cross-resistance was observed with some current first-line anti-TB drugs, since it similarly inhibited the growth of multidrug resistant (MDR) clinical isolates. The compound showed a good selectivity for mycobacteria since it did not inhibit the growth of selected Gram-positive and Gram-negative bacteria. It also showed synergistic activity with rifampicin (RIF) and additive activity with isoniazid (INH) and ethambutol (EMB). Additional time-kill studies showed that the compound is bacteriostatic to mycobacteria, but cytotoxic to the Chinese Additional Supporting Information may be found in the online version of this article.
612
IUBMB LifeHamster Ovarian (CHO) cell line. From a second generation library, two compounds showed improved anti-TB activity against M. tuberculosis H37Rv and decreased CHO cell cytotoxicity. The compounds exhibited MIC values of 2.62 mg/mL (5.6 mM) and 3.07 mg/mL (5.6 mM) respectively. The improved cytotoxicity against CHO cell line of the two compounds ranged from IC 50 5 38.24 mg/mL to IC 50 5 45.58 mg/mL when compared to the most active first-generation compound (IC 50 5 1.82 mg/mL). The two second generation leads with selectivity indices (SI) of 14.64 and 14.85 respectively, warrant further development as anti-TB drug candidates. V C 2016 IUBMB Life, 68(8):612-620, 2016
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