New insights into the SAR and drug combination synergy of 2-(quinolin-4-yloxy)acetamides against Mycobacterium tuberculosis

• DOI: 10.1016/j.ejmech.2016.11.048
• Publication Date: 2016-11-23T03:17:07Z
• Authors: Bruno Couto Giacobbo; Kenia Pissinate; Valnês Rodrigues-...; Anne Drumond Villela; Estêvão Silveira ...; Bruno Lopes Abbadi; Fernanda Teixeira...; Nathalia Sperotto; Rogério Valim Tri...; Davi Fernando Back; Maria Martha Campos; Luiz Augusto Basso; Pablo Machado; Diógenes Santiago...
• Keywords: 0301 basic medicine; Macrophages; Antitubercular Agents; Drug Synergism; Microbial Sensitivity Tests; Mycobacterium tuberculosis; 3. Good health; Mice; Structure-Activity Relationship; 03 medical and health sciences; RAW 264.7 Cells; Acetamides; Drug Resistance, Bacterial; Quinolines; Animals; Humans

2-(Quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (MIC) values against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains in the submicromolar range. Furthermore, the most active compounds had no apparent toxicity to mammalian cells, and they showed intracellular activities similar to those of isoniazid and rifampin in a macrophage model of Mtb infection. Use of the checkerboard method to investigate the association profiles of lead compounds with first- and second-line antituberculosis drugs showed that 2-(quinolin-4-yloxy)acetamides have a synergistic effect with rifampin. Ultimately, the good permeability, moderate rates of metabolism and low risk of drug-drug interactions displayed by some of the synthesized compounds indicate that 2-(quinolin-4-yloxy)acetamides may yield candidates to use in the development of novel alternative therapeutics for tuberculosis treatment.