Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agents

Ana Flávia Borsoi, Josiane Delgado Paz, Bruno Lopes Abbadi, Fernanda Souza Macchi, Nathalia Sperotto, Kenia Pissinate, Raoní S Rambo, Alessandro Silva Ramos, Diana Machado, Miguel Viveiros, Cristiano Valim Bizarro, Luiz Augusto Basso, Pablo Machado

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33 Citations (Scopus)


Using a classical molecular simplification approach, a series of 36 quinolines were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (M. tuberculosis) growth. Structure-activity relationship (SAR) studies leaded to potent antitubercular agents, with minimum inhibitory concentration (MIC) values as low as 0.3 μM against M. tuberculosis H37Rv reference strain. Furthermore, the lead compounds were active against multidrug-resistant strains, without cross-resistance with some first- and second-line drugs. Testing the molecules against a spontaneous mutant strain containing a single mutation in the qcrB gene (T313A) indicated that the synthesized quinolines targeted the cytochrome bc1 complex. In addition, leading compounds were devoid of apparent toxicity to HepG2 and Vero cells and showed moderate elimination rates in human liver S9 fractions. Finally, the selected structures inhibited M. tuberculosis growth in a macrophage model of tuberculosis infection. Taken together, these data indicate that this class of compounds may furnish candidates for the future development of antituberculosis drugs.

Original languageEnglish
Article number112179
Pages (from-to)112179-112189
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Early online date21 Feb 2020
Publication statusPublished - 15 Apr 2020


  • Cytochrome bc(1) complex
  • Intracellular activity
  • Molecular simplification
  • Multidrug-resistant strains
  • Mycobacterium tuberculosis
  • SAR


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