Searching for New Leads for Tuberculosis: Design, Synthesis, and Biological Evaluation of Novel 2‑Quinolin-4-yloxyacetamides

In this study, a
new series of more than 60 quinoline derivatives
has been synthesized and evaluated against Mycobacterium
tuberculosis (H37Rv). Apart from the SAR exploration
around the initial hits, the optimization process focused on the improvement
of the physicochemical properties, cytotoxicity, and metabolic stability
of the series. The best compounds obtained exhibited MIC values in
the low micromolar range, excellent intracellular antimycobacterial
activity, and an improved physicochemical profile without cytotoxic
effects. Further investigation revealed that the amide bond was the
source for the poor blood stability observed, while some of the compounds
exhibited hERG affinity. Compound 83 which contains a
benzoxazole ring instead of the amide group was found to be a good
alternative, with good blood stability and no hERG affinity, providing
new opportunities for the series. Overall, the obtained results suggest
that further optimization of solubility and microsomal stability of
the series could provide a strong lead for a new anti-TB drug development
program.