The emergence and the dissemination of multidrug-resistant bacteria constitute a major public health issue. Among incriminated Gram-negative bacteria, Pseudomonas aeruginosa has been designated by the WHO as a critical priority threat. During the infection process, this pathogen secretes various virulence factors in order to adhere and colonize host tissues. Furthermore, P. aeruginosa has the capacity to establish biofilms that reinforce its virulence and intrinsic drug resistance. The regulation of biofilm and virulence factor production of this micro-organism is controlled by a specific bacterial communication system named Quorum Sensing (QS). The development of anti-virulence agents targeting QS that could attenuate P. aeruginosa pathogenicity without affecting its growth seems to be a promising new therapeutic strategy. This could prevent the selective pressure put on bacteria by the conventional antibiotics that cause their death and promote resistant strain survival. This review describes the QS-controlled pathogenicity of P. aeruginosa and its different specific QS molecular pathways, as well as the recent advances in the development of innovative QS-quenching anti-virulence agents to fight anti-bioresistance.

There is an urgent need to propose effective treatments for Alzheimer’s disease (AD). Although the origin of the disease is poorly understood, several therapeutic options have been proposed. The new therapeutic approaches targeting biometal-mediated neurodegenerative pathways appear to be interesting ones. As a continuation of our preceding studies, two novel series of advanced glycation endproducts (AGE)/advanced lipid peroxidation endproducts (ALE) inhibitors have been developed as multifunctional scavengers. This extended work allowed us to highlight the new hydroxypyridinone-diamine hybrid IIa-3 bearing a C4 alkyl linker between the two pharmacophores. This derivative exhibited preserved potent capacities to trap reactive carbonyl species (vicinal diamine function) as well as reactive oxygen species and transition metals (hydroxypyridinone moiety) in comparison with previously described lead compound 1. In addition, its good predicted absorption, distribution, metabolism and excretion (ADME) properties were correlated with a better efficacy to inhibit in vitro methylglyoxal-induced apoptosis in neuronal-like PC12 cells. This new promising agent revealed improved druglikeness and ability to prevent biometal-mediated oxidative and carbonyl stress amplification involved in AD pathogenesis.

Multi-drug resistant ESKAPEE pathogens are responsible for various nosocomial infections. Considering this serious threat to public health, new efficient treatments are urgently needed. 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. Interestingly, HQNO appears to be a potent respiratory chain inhibitor for various competing microorganisms such as S. aureus. 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. 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-4chloroquinoline precursors will be described in the presentation.

Inhibitory properties of these new compounds on biofilm formation have been evaluated on P. aeruginosa PAO1 strain using purple crystal dyeing (Fig. 4A). Compounds 4d and 4e showed