Novel Isoniazid-Carborane Hybrids Active In Vitro against Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is a severe infectious disease with high mortality and morbidity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (INH) remains the key and effective component in the therapeutic regimen recommended by World Health Organization (WHO). A series of isoniazid-carborane derivatives containing 1,2-dicarba-<i>closo</i>-dodecaborane, 1,7-dicarba-<i>closo</i>-dodecaborane, 1,12-dicarba-<i>closo</i>-dodecaborane, or 7,8-dicarba-<i>nido</i>-undecaborate anion were synthesized for the first time. The compounds were tested <i>in vitro</i> against the <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) H37Rv strain and its mutant (D<i>katG</i>) defective in the synthesis of catalase-peroxidase (KatG). <i>N</i>'-((7,8-dicarba-<i>nido</i>-undecaboranyl)methylidene)isonicotinohydrazide (<b>16</b>) showed the highest activity against the wild-type <i>Mtb</i> strain. All hybrids could inhibit the growth of the Δ<i>katG</i> mutant in lower concentrations than INH. <i>N</i>'-([(1,12-dicarba-<i>closo</i>-dodecaboran-1yl)ethyl)isonicotinohydrazide (<b>25</b>) exhibited more than 60-fold increase in activity against <i>Mtb</i> D<i>katG</i> as compared to INH. This compound was also found to be noncytotoxic up to a concentration four times higher than the minimum inhibitory concentration 99% (MIC₉₉) value.