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. 2019 Aug;80(5):566-572.
doi: 10.1002/ddr.21531. Epub 2019 Mar 20.

8-Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis

Joshua O Odingo  1 , Julie V Early  1 , Jake Smith  1 , James Johnson  1 , Mai A Bailey  1 , Megan Files  1 , Junitta Guzman  1 , Juliane Ollinger  1 , Aaron Korkegian  1 , Anuradha Kumar  1 , Yulia Ovechkina  1 , Tanya Parish  1
Affiliations

8-Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis

Joshua O Odingo et al. Drug Dev Res. 2019 Aug.

Abstract

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 (IC50 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.

Keywords: Mycobacterium tuberculosis; tuberculosis; antibacterial; hydroxyquinoline; structure-activity relationship.

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Conflict of interest statement

The authors declare they have no conflict of interest.

Figures

Figure 1
Figure 1
Bactericidal activity of compounds against replicating M. tuberculosis. Compounds (24) (top) and (4) (bottom) were tested for their ability to kill M. tuberculosis under replicating conditions. M. tuberculosis was cultured in 7H9‐OADC‐Tw medium in the presence of compounds from 1× MIC to 10× MIC (concentrations given in μM). Viable bacteria were counted by measuring CFUs. Data are the mean ± SD from two independent experiments
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