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.

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Pyrazole derivatives R 0180 4-Substituted Indazoles as New Inhibitors of Neuronal Nitric Oxide Synthase. -Halogenated indazoles such as (III) are obtained by diazotization of methylanilines (I), followed by cyclization of the resulting diazonium tetrafluoroborate salts (II) through promotion of potassium acetate and a crown ether. Position 4 of the new inhibitors seems to be as important as position 7 to confer inhibitory properties against NOS activity. The importance of position 4 is further demonstrated by the synthesis of the potent inhibitor 4-nitroindazole, which is obtained in the same manner from o-toluidine. The in vitro properties of the inhibitors are associated with an in vivo efficiency, as attested by potent antinociceptive effects following systemic administration. -(BOULOUARD, M.; SCHUMANN-BARD, P.; BUTT-GUEULLE, S.; LOHOU, E.; STIEBING, S.; COLLOT*, V.; RAULT, S.; Bioorg. Med. Chem. Lett. 17 (2007) 11, 3177-3180; Cent. Etud. Rech. Med. Normandie, UFR Sci. Pharm., Univ. Caen, F-14032 Caen, Fr.; Eng.) -H. Hoennerscheid 40-126

Overexpression of efflux pumps extruding antibiotics currently used for the treatment of Acinetobacter baumannii infections has been described as an important mechanism causing antibiotic resistance. The first aim of this work was to phenotypically evaluate the overexpression of efflux pumps on a collection of 124 ciprofloxacin resistant A. baumannii strains. An overexpression of genes encoding one or more efflux pumps was obtained for 19 out of the 34 strains with a positive phenotypic efflux (56%). The most frequent genes overexpressed were those belonging to the RND family, with adeJ being the most prevalent (50%). Interestingly, efflux pump genes coding for MATE and MFS families were also overexpressed quite frequently: abeM (32%) and abaQ (26%). The second aim was to synthesize 1-(1-NaphthylMethyl)-Piperazine analogs as potential new efflux pump inhibitors and biologically evaluate them against strains with a positive phenotypic efflux. Quinoline and pyridine analogs were found to be more effective than their parent compound 1-(1-NaphthylMethyl)-Piperazine. Stereochemistry also played an important part in the inhibitory activity as quinoline derivative ( R )-3a was identified as being the most effective and less cytotoxic. Its inhibitory activity was also correlated to the number of efflux pumps expressed by a strain. The results obtained in this work suggest that quinoline analogs of 1-(1-NaphthylMethyl)-Piperazine are promising leads in the development of new anti- Acinetobacter baumannii therapeutic alternatives, in combination with antibiotics for which an efflux-mediated resistance is suspected.

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.

An efficient synthesis of various N-substituted 3-aminoindazoles using Buchwald-Hartwig C-N coupling reaction is described. Several parameters were varied, including the nature of the halogen atom and the protecting group of the starting materials, as well as the effects of the catalyst system, base, solvent, and reaction time. The efficiency of microwave versus conventional heating was also compared to test the outcome of the reaction. Thus, by applying this recent knowledge about metal-catalyzed aminations, an alternative for the direct synthesis of primary 3-aminoindazoles has been provided.