Design, synthesis and antitubercular activity of 4-alkoxy-triazoloquinolones able to inhibit the M. tuberculosis DNA gyrase

Eur J Med Chem. 2019 Jan 1;161:399-415. doi: 10.1016/j.ejmech.2018.10.031. Epub 2018 Oct 17.


A number of new F-triazolequinolones (FTQs) and alkoxy-triazolequinolones (ATQs) were designed, synthesized and evaluated for their activity against Mycobacterium tuberculosis H37Rv. Five out of 21 compounds exhibited interesting minimum inhibitory concentration (MIC) values (6.6-57.9 μM), ATQs generally being more potent than FTQs. Two ATQs, 21a and 30a, were endowed with the best anti-Mtb potency (MIC = 6.9 and 6.6 μM, respectively), and were not cytotoxic in a Vero cell line. Tested for activity against M. tuberculosis DNA gyrase in a DNA supercoiling activity assay, 21a and 30a showed IC50 values (27-28 μM) comparable to that of ciprofloxacin (10.6 μM). 21a was next selected for screening against several Mtb strains obtained from clinical isolates, including multi-drug-resistant (MDR) variants. Importantly, this compound was effective in all cases, with very promising MIC values (4 μM) in the case of some isoniazid/rifampicin-resistant Mtb strains. Finally, computer-based simulations revealed that the binding mode of 21a in the Mtb gyrase cleavage core complexed with DNA and the relevant network of intermolecular interactions are utterly similar to those described for ciprofloxacin, yielding a molecular rationale for the comparable anti-mycobacterial and DNA gyrase inhibition activity of this quinolone.

Keywords: Antitubercular activity; In vitro and in silico studies; M. tuberculosis DNA gyrase; M. tuberculosis clinical strains; Triazoloquinolones.

MeSH terms

  • Animals
  • Antifungal Agents / chemical synthesis
  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology*
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry
  • Antitubercular Agents / pharmacology*
  • Chlorocebus aethiops
  • DNA Gyrase / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / enzymology
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Saccharomyces cerevisiae / drug effects
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*
  • Vero Cells


  • Antifungal Agents
  • Antitubercular Agents
  • Quinolones
  • Topoisomerase II Inhibitors
  • DNA Gyrase