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 3, which have been identified as good candidates against ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli) bacteria. Secondly, a new series 4 was designed and assessed against the same bacteria strains, taking the pair of enantiomers 3m/3n as the lead. More than twenty compounds 4 were prepared through a five-step asymmetric synthesis with good enantiomeric excesses (>90%). Interestingly, all compounds of series 3 were efficient on M. avium with MIC = 2–16 µg/mL, while series 4 was less active. Both series 3 and 4 were generally more active than mefloquine against the ESKAPEE bacteria. The quinolines 4 were either active against Gram-positive bacteria (MIC ≤ 4 µg/mL for 4c–4h and 4k/4l) or E. coli (MIC = 32–64 µg/mL for 4q–4v) according to the global lipophilicity of these compounds.

Courtioux (2020) Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substitutedaminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4bis[(substituted-aminomethyl)phenyl]quinazoline derivatives,

The X-ray crystal structure of 2,8-bis(trifluoromethyl)-4-vinylquinoline, a key intermediate in the synthesis of potent antimalarial agents, has been established. It crystallizes in the monoclinic space group P21/c with cell parameters a = 16.678(2)Å, b = 17.492(7)Å, c = 8.286(4)Å, β = 97.50(2), V = 2396.5(16)Å 3 and Z = 4. The crystal structure was refined to final values of R1 = 0.1043 and wR2 = 0.2207. An X-ray crystal structure analysis revealed that each molecule features intermolecular C-H•••F hydrogen bonds and halogen halogen-type I interactions.

1 Graphical Abstract Use one slide Synthesis, biological evaluation and membranotropic properties of quinoline-antimicrobial peptide conjugates as antibacterial drugs 2 Name MIC (µM) HC 50 (µM) S. aureus CIP103.429 E. faecalis CIP 103214 E. coli DSM 1103 P. aeruginosa DSM 1117 Dassonville-Klimpt, A.; Sonnet, P.; Mullié, C. Side chain length is more important than stereochemistry in the antibacterial activity of enantiomerically pure 4-aminoalcohol quinoline derivatives. J. Antibiot. (Tokyo) 2013, 66, 683-686. 4. Laumaillé, P.; Dassonville-Klimpt, A.; Peltier, F.; Mullié, C.; Andréjak, C.; Da-Nascimento, S.; Castelain, S.; Sonnet, P.; Synthesis and study of new quinolineaminoethanols as anti-bacterial drugs, Pharmaceuticals 2019, 12(2), 91. 5. Strøm, M. B. et al. The Pharmacophore of Short Cationic Antibacterial Peptides, 2003, 46, 3-6.