Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through , , and approaches.

Tuberculosis remains a serious global health threat, exacerbated by the rise of resistant strains. This study investigates the potential of two benzofuroxan () derivatives, 5n and 5b, as targeted treatments for MDR-TB using , , and methodologies. analyses showed that compounds have significant activity against H37Rv, with 5n standing out with a MIC of 0.09 ± 0.04 μM. Additionally, their efficacy against MDR and pre-XDR strains was superior compared to commercial drugs. These compounds have a narrow spectrum for mycobacteria, which helps avoid dysbiosis of the gut microbiota, and they also exhibit high selectivity and low toxicity. Synergism studies indicate that derivatives could be combined with rifampicin to enhance treatment efficacy and reduce its duration. Scanning electron microscopy revealed severe damage to the morphology of following treatment with 5n, showing significant distortions in the bacillary structures. Whole-genome sequencing of the 5n-resistant isolate suggests resistance mechanisms mediated by the Rv1855c gene, supported by studies. studies showed that the 5n compound reduced the pulmonary load by 3.0 log CFU/mL, demonstrating superiority over rifampicin, which achieved a reduction of 1.23 log CFU/mL. In conclusion, derivatives, especially 5n, effectively address resistant infections caused by , suggesting they could be a solid foundation for future therapeutic developments against MDR-TB.