ESKAPEE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli) responsible for various nosocomial infections, constitute an important group of multi-drug resistant bacteria. To overcome this serious threat to public health, the development of antimicrobial molecules active towards new pharmacological targets appears as a promising strategy. For this purpose, bacterial communication systems, called Quorum Sensing (QS), could be interrupt to disturb the expression of virulence factors, the multiplication of bacteria and/or the development of biofilms in response to environmental factors. The pqs system, one of the three main QS circuits of P. aeruginosa, is based on two small signalling molecules, the Pseudomonas quinolone signal (PQS) and its precursor 2-heptyl-4(1H)-quinolone (HHQ). P. aeruginosa internalizes extracellular PQS synthesized by neighboring bacterial cells. High cellular concentration of PQS then activates the transcriptional regulator PqsR which triggers the synthesis of enzymes involved in the metabolic HHQ/PQS pathway. During this process, HHQ is converted into PQS and leads to the regulation of P. aeruginosa medium. Furthermore, P. aeruginosa produces a secondary metabolite through this PQS pathway, the 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), which is toxic for various competing microorganisms such as S. aureus. In fact, HQNO disrupts the respiratory chain of many bacteria at the cytochrome bc1 complex what provokes reactive oxygen species accumulation and finally apoptosis. Recently, the interest of quinolone scaffold in the design of QS and respiratory chain inhibitors has emerged. HHQ analogues such as 6-nitro-HHQ-3-carboxamide have been described as PqsR antagonists and 2-phenyl or pyridinyl-4-quinolone series have been respectively identified as Mycobacterium tuberculosis and Plasmodium falciparum type II NADH/quinone oxidoreductase (NDH-2) inhibitors. Taking these studies into account, we aim to develop a new 2-heteroaryl-4-quinolone family with potential antibacterial properties. In the poster, the synthesis of first expected derivatives carrying out metal-catalyzed C-C or C-N coupling reactions from 2-bromo-4-chloroquinoline precursors is presented.

New 2-heteroaryl-4-quinolones as potential antibiotics targeting multi-drug resistant ESKAPEE pathogen communication systems

2019 Fall National Meeting

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