6-hydrogen-8-methylquinolones active against replicating and non-replicating Mycobacterium tuberculosis.
The screening of an in-house quinolones library against Mycobacterium tuberculosis (Mtb) H(37) Rv, followed by a first cycle of optimization, yielded 6-hydrogen-8-methyl derivatives endowed with good potency. The antitubercular activity also encompassed the bacteria in a non-replicating state (NRP-TB) with minimum inhibitory concentration values lower than those of the reference agent, moxifloxacin. Among the best compounds, 11w and 11ai, characterized by a properly substituted piperidine at the C-7 position, were active against single-drug-resistant (SDR-TB) Mtb strains, maintaining overall good potency also against ciprofloxacin-resistant Mtb. This study expands the body of SAR around antitubercular quinolones leading to reconsider the role played by the usual fluorine atom at the C-6 position. Further elaboration of the 6-hydrogen-8-methylquinolone scaffold, with a particular focus on the C-7 position, is expected to give even more potent congeners holding promise for shortening the current anti-TB regimen.
Oriana
O
Tabarrini
Stefano
S
Sabatini
Serena
S
Massari
Marco
M
Pieroni
Scott G
SG
Franzblau
Violetta
V
Cecchetti
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D018432:Drug Resistance, Multiple; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy; D014709:Vero Cells
D000995:Antitubercular Agents; D011804:Quinolines