Synthesis of novel iminosugars and study of their interactions with glycosidases.

Les iminosucres constituent une classe de glycomimétiques particulièrement prometteuse pour le traitement de nombreuses maladies, grâce à leur capacité à inhiber et/ou à stabiliser des glycosidases. Ces enzymes, présentes dans tous les organismes vivants, sont impliquées dans différents processus biologiques et sont des cibles thérapeutiques importantes pour le traitement de diverses maladies. Identifier de nouveaux iminosucres sélectifs vis-à-vis d’un type spécifique de glycosidases représente à l’heure actuelle un réel défi scientifique. Le relever est une nécessité pour la mise sur le marché de nouvelles thérapies contre le diabète, les infections virales, certains cancers et certaines maladies lysosomales. L’objectif de cette thèse a été d’une part de développer des voies de synthèse d’iminosucres bicycliques à squelettes quinolizidine et conidine comportant un substituant hydroxyméthyle en jonction de cycles, et d’autre part d’étudier leurs interactions avec différentes glycosidases.Cinq quinolizidines polyhydroxylées et quatre conidines polyhydroxylées inédites ont été synthétisées, à partir d’une même cétonitrone dérivée du L-sorbose. Les étapes clés de la synthèse des quinolizidines sont une C-allylation diastéréosélective de cette nitrone et une cyclisation par métathèse d’oléfines. En utilisant cette approche, d’autres analogues pourront être synthétisés dans le futur en exploitant diverses possibilités de fonctionnalisation de l’alcène formé par métathèse cyclisante. Les conidines polyhydroxylées ont été synthétisées à partir de b-lactames bicycliques, obtenus soit par une cycloaddition 1,3-dipolaire suivie d’un réarrangement des isoxazolines formées (méthode de DeShong) soit par la réaction de Kinugasa. Les synthèses ici développées comportent peu d’étapes et ont donné accès aux iminosucres cibles avec de bons rendements.Le pouvoir inhibiteur de ces iminosucres a été évalué sur un panel de glycosidases commerciales et sur des glycosidases humaines. La plupart sont des inhibiteurs sélectifs des a-glucosidases. Des études conformationelles par RMN et par calcul DFT, ainsi que des études cristallographiques des complexes iminosucre/a-glucosidase ont permis de comprendre le mode d’interaction de notre nouvelle famille d’iminosucres avec ces enzymes.Iminosugars are a promising class of glycomimetics for the treatment of many diseases due to their ability to inhibit and/or stabilize glycosidases. These enzymes, which are present in all living organisms, are involved in different biological processes and are important therapeutic targets for the treatment of various diseases. Nowadays, identifying new selective iminosugars matching with a specific type of glycosidase represents a real scientific challenge. Tackling this challenge is crucial for the delivery of new therapies against diabetes, viral infections, certain cancers and certain lysosomal diseases. The objective of this thesis was firstly to develop synthetic routes towards quinolizidine and conidine iminosugars bearing a hydroxymethyl substituent at the ring junction, and secondly to study their interactions with different glycosidases.Five polyhydroxylated quinolizidines and four polyhydroxylated conidines were obtained from the same L-sorbose-derived ketonitrone. The key steps in the synthesis of quinolizidines are a diastereoselective C-allylation of this nitrone and a ring-closing olefin metathesis. Applying this approach, other analogues can be synthesized in the future by exploiting various possibilities for functionalization of the alkene formed upon ring-closing metathesis. The polyhydroxylated conidines were synthesized from bicyclic b-lactams, obtained either by a 1,3-dipolar cycloaddition followed by rearrangement of the formed isoxazolines (DeShong method) or by the Kinugasa reaction. The syntheses developed herein involve few steps and give access to the target iminosugars with good yields.The inhibitory potency of these iminosugars was evaluated on a panel of commercial and on human glycosidases. Most are selective inhibitors of a-glucosidases. Conformational studies by NMR and DFT calculations, as well as crystallographic studies of iminosugar/a-glucosidase complexes, clarified the mode of interaction of our new family of iminosugars with these enzymes

Polyhydroxylated Quinolizidine Iminosugars as Nanomolar Selective Inhibitors of α-Glucosidases

International audienc

Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria

Antimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely resistant to known antibiotics. AMR is caused by several mechanisms, among which the (over)expression of multidrug efflux pumps plays a central role. Multidrug efflux pumps are transmembrane transporters, naturally expressed by Gram-negative bacteria, able to extrude and confer resistance to several classes of antibiotics. Targeting them would be an effective way to revive various options for treatment. Many efflux pump inhibitors (EPIs) have been described in the literature; however, none of them have entered clinical trials to date. This review presents eight families of EPIs active against Escherichia coli or Pseudomonas aeruginosa. Structure–activity relationships, chemical synthesis, in vitro and in vivo activities, and pharmacological properties are reported. Their binding sites and their mechanisms of action are also analyzed comparatively

Optimization of pyridylpiperazine-based inhibitors of the Escherichia coli AcrAB-TolC efflux pump

Multidrug–resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a critical driver. We have previously described pyridylpiperazines as a novel class of allosteric inhibitors of E. coli AcrB which bind to a unique site in the protein transmembrane domain, allowing for the potentiation of antibiotic activity. Here, we show a rational optimization of pyridylpiperazines by modifying three specific derivatization points of the pyridine core to improve the potency and the pharmacokinetic properties of this chemical series. In particular, this work found that the introduction of a primary amine to the pyridine through ester (29, BDM91270) or oxadiazole (44, BDM91514) based linkers allowed for analogues with improved antibiotic boosting potency through AcrB inhibition. In vitro studies, using genetically engineered mutants, showed that this improvement in potency is mediated through novel interactions with distal acidic residues of the AcrB binding pocket. Of the two leads, compound 44 was found to have favorable physico-chemical properties and suitable plasma and microsomal stability. Together, this work expands the current structure-activity relationship data on pyridylpiperazine efflux pump inhibitors, and provides a promising step towards future in vivo proof of concept of pyridylpiperazines as antibiotic potentiators

On the Hunt for Next-Generation Antimicrobial Agents: An Online Symposium Organized Jointly by the French Society for Medicinal Chemistry (Société de Chimie Thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) on 9–10 December 2021

The restrictions posed by the COVID-19 pandemic obliged the French Society for Medicinal Chemistry (Société de chimie thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) to organize their joint autumn symposium (entitled “On the hunt for next-generation antimicrobial agents”) online on 9–10 December 2021. The meeting attracted more than 200 researchers from France and abroad with interests in drug discovery, antimicrobial resistance, medicinal chemistry, and related disciplines. This review summarizes the 13 invited keynote lectures. The symposium generated high-level scientific dialogue on the most recent advances in combating antimicrobial resistance. The University of Lille, the Institut Pasteur de Lille, the journal Pharmaceuticals, Oxeltis, and INCATE, sponsored the event

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use