Other Diamine Derivatives

Another compound, SQ-73 (Fig. 23; 9e), having a moderate MIC at 12.5 p.M but a better therapeutic index (for macrophage toxicity) of 6.4, was studied further as this compound exhibited better activity in macrophages. In vivo studies with SQ-73 exhibited moderate tissue distribution [271]. A structurally related dipiperidine class of compounds was also recently reported, with the most effective compound from this series exhibiting an MIC of 6.25 p.M against MTb [281]. After further optimization and analysis of the dipiperidine library, the compound SQ-609 (Fig. 23; 9f) was selected as the most promising in the class. This compound has moderate in vitro cytotoxicity in cultured mammalian cells and a suitable therapeutic window. SQ-609 has shown efficacy against intracellular MTb, good aqueous solubility, and oral bioavailability. In murine studies, SQ-73 (5 mg/kg), SQ-109

(10 mg/kg), and SQ-609 (10 mg/kg) all exhibited activity similar to INH (25 mg/kg) after 3 weeks of treatment [281].

Was this article helpful?

0 0

Post a comment