8‐Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis

There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8‐hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure–activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8‐hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 μM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub‐family of 2‐styryl‐substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC(50) of <100 μM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8‐hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.