Design, Synthesis, and Antitubercular Activity Evaluation of Novel Nitroimidazole Derivatives

The development of novel antitubercular agents represents a critical strategy against drug-resistant tuberculosis (TB). In this study, we designed and synthesized a series of novel nitroimidazole derivatives from Delemanid by introducing an aliphatic spirocyclic moiety. Most compounds demonstrated potent in vitro antitubercular activity with negligible cytotoxicity. Compound TB-212 exhibited superior activity against Mtb H37Ra over Delamanid (MIC values: 0.2 vs 1.0 ng/mL), and maintained robust efficacy against clinical drug-resistant strains. Importantly, TB-212 displayed significantly improved solubility, higher permeability in Caco-2 cell and a lower risk of cardiotoxicity. PK studies revealed that TB-212 absorbed rapidly following oral administration, with drug exposure exhibiting a favorable linear dose-proportional manner, distinct from the nonlinear PK profile of Delamanid. In a mouse model of TB, TB-212 outperformed Delamanid in terms of in vivo therapeutic efficacy. Collectively, these findings highlight the promising therapeutic potential of TB-212, particularly for the treatment of drug-resistant TB.