Synthesis of novel 8-methodyquinoline derivatives and in vitro antibacterial activity

Abstract

The resistance of bacteria to antibiotics has become a worldwide concern and the development of new agents is of particular interest. Quinolines derivatives have shown activity against several microorganism and the presence of substituent on the quinoline ring seems to modulate the activity and the toxicity. Thus, the purpose of this study was the synthesis and characterization of the novel series of 8-methoxyquinoline derivatives and evaluation of in vitro antibacterial activity against ATCC strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter aerogenes, Shigella flexneri, Enterococcus faecalis, and Staphylococcus aureus. The commercial available clioquinol 3 was used to prepare 5-chloro-7-amino-8-methoxyquinoline derivatives (5a-5e) with a two-step synthesis: methylation of 3 to 5-chloro-7-iodo-8-methoxyquinoline 4 and palladium-catalyzed cross-coupling reaction to amination at position 7 in 50-66% of overall yield. The compounds prepared were characterized by FT-IR, 1H and 13C NMR. The nitroxoline 2, synthetized from 8-hydroxyquinoline in 54% yield, and 3 were used as positive controls for in vitro evaluation of antibacterial activity for the novel series by broth microdilution assay. The compounds 5a and 5b presented activity against two Gram-positive bacteria E. faecalis and S. aureus, including the Methicillin resistant strain of S. aureus (ATCC 33591). However just the compound 5b, that bear an electron withdrawing group (EWG) at para-position of the 7-aniline, presented activity comparable to the positive controls, with value of minimal inhibitory concentration (MIC) of 4-8 μg/mL for those strains. Thus, this compound has the potential to be developed as an antibacterial agent.