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.
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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