| Summary: | The lack of antibiotics with a novel mode of action associated with the spread of drug resistant bacteria make the fight against infectious diseases particularly challenging. A quinoline core is found in several anti-infectious drugs, such as mefloquine and bedaquiline. Two main objectives were set in this work. Firstly, we evaluated the anti-mycobacterial properties of the previous quinolines <b>3</b>, which have been identified as good candidates against ESKAPEE (<i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, <i>Enterobacter</i> spp. and <i>Escherichia coli</i>) bacteria. Secondly, a new series <b>4</b> was designed and assessed against the same bacteria strains, taking the pair of enantiomers <b>3m</b>/<b>3n</b> as the lead. More than twenty compounds <b>4</b> were prepared through a five-step asymmetric synthesis with good enantiomeric excesses (>90%). Interestingly, all compounds of series <b>3</b> were efficient on <i>M. avium</i> with MIC = 2−16 µg/mL, while series <b>4</b> was less active. Both series <b>3</b> and <b>4</b> were generally more active than mefloquine against the ESKAPEE bacteria. The quinolines <b>4</b> were either active against Gram-positive bacteria (MIC ≤ 4 µg/mL for <b>4c</b>−<b>4h</b> and <b>4k</b>/<b>4l</b>) or <i>E. coli</i> (MIC = 32−64 µg/mL for <b>4q</b>−<b>4v</b>) according to the global lipophilicity of these compounds.
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