Development of new 2-heteroaryl-4-quinolones as potential antibiotics targeting multi-​drug resistant ESKAPEE pathogens

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Multi-drug resistant ESKAPEE pathogens are responsible for various nosocomial infections. Considering this serious threat to public health, new efficient treatments are urgently needed.1 The bacterial communication systems, called quorum sensing (QS), constitute a pool of new promising pharmacological targets for the development of antimicrobial molecules. The inhibition of QS could disrupt several intra/inter-species protective interactions (bacterial multiplication, biofilm formation) and virulence pathways. The intervention of three main small signaling molecules was described in the pqs intercellular communication system of P. aeruginosa : the Pseudomonas quinolone signal (PQS), its precursor 2-heptyl-4(1H)-quinolone (HHQ) and the 2‑heptyl‑4‑hydroxyquinoline-N-oxide (HQNO) as a secondary metabolite from this pathway.2 Interestingly, HQNO appears to be a potent respiratory chain inhibitor for various competing microorganisms such as S. aureus.3 Furthermore, HHQ analogues and different 2-heteroaryl-4-quinolone series revealed efficient as QS inhibitors (PQS receptor antagonists) or as type II NADH/quinone oxidoreductase inhibitors.4,5,6 Taking these studies into account, the interest of the quinolone scaffold in the design of QS and respiratory chain inhibitors has emerged. In this context, we aim to develop new antibacterial 2‑heteroaryl‑4‑quinolone series. The synthesis of the first series carrying out pallado-catalyzed C-C or C-N coupling reactions from 2-bromo-4-chloroquinoline precursors will be described in the presentation. Bibliographic references: (1) Expert Rev. Anti Infect. Ther., 2013, 11(3), 297-308 ; (2) Org. Biomol. Chem., 2018, 16, 169-181 ; (3) Curr. Biol., 2016, 26, 195-206 ; (4) Org. Biomol. Chem., 2017, 15, 4620-4630 ; (5) J. Med. Chem., 2012, 55, 1844-1857; (6) J. Med. Chem., 2017, 60, 3703-3726.