ABSTRACT
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.
Subject(s)
Acetamides/chemistry , Acetamides/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Quinolines/chemistry , Acetamides/chemical synthesis , Acetamides/metabolism , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/metabolism , Drug Resistance, Bacterial/drug effects , Drug Synergism , Humans , Macrophages/drug effects , Macrophages/microbiology , Mice , Microbial Sensitivity Tests , RAW 264.7 Cells , Structure-Activity RelationshipABSTRACT
2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 µM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 µM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 µM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.
