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International audience; A small library of molecules combining indolizine and N-alkyl pyridinium was synthesized and evaluated in a multi-target-directed-ligand strategy for Alzheimer's disease (AD) treatment. The new compounds were classified in three series depending on the number of methylene residues linking the two heterocycles (Ind-PyCx with x = 0, 2 or 3). The molecules were synthesized from the corresponding bis-pyridines by two-step formation of the indolizine core including mono-alkylation of pyridine and 1,3-dipolar cycloaddition with an alkylpropiolate. Their activities against AD's key-targets were evaluated in vitro: acetyl- and butyrylcholinesterase (AChE and BChE) inhibition, antioxidant properties and inhibition of amyloid fibril formation. None of the three series showed significant activities against all the targets. The Ind-PyC2 and Ind-PyC3 series are active on eeAChE and hAChE (µM IC50 values). Most of the positively charged molecules from these two series also appeared active against eqBChE, however they lost their activity on hBChE. Comparative molecular modeling of 13 and 15 docked in hAChE and hBChE highlighted the importance of the substituent (p-methoxybenzoyl or methyloxycarbonyl, respectively) located on the indolizine C-3 for the binding. The larger molecule 13 fits more tightly at the active site of the two enzymes than 15 that shows a larger degree of freedom. The Ind-PyC2 and Ind-PyC3 hybrids displayed some antioxidant activity when tested at 750 µg/mL (up to 95% inhibition of DPPH radical scavenging for 10). In both series, most hybrids were also able to interact with amyloid fibers, even if the inhibitory effect was observed at a high 100 µM concentration. The Ind-PyC0 molecules stand out completely due to their spectroscopic properties which prevent their evaluation by Ellman’s and ThT assays. However, these molecules showed interesting features in the presence of preformed fibers. In particular, the strong increase in fluorescence of 3 in the presence of amyloid fibers is very promising for its use as a fibrillation fluorescent reporter dye.

Cellulose nanofibrils (CNF) are renewable bio-based materials with high specific area, which makes them ideal candidates for multiple emerging applications including for instance on-demand drug release. However, in-depth chemical and structural characterization of the CNF surface chemistry is still an open challenge, especially for low weight percentage of functionalization. This currently prevents the development of efficient, cost-effective and reproducible green synthetic routes and thus the widespread development of targeted and responsive drug-delivery CNF carriers. We show in this work how we use dynamic nuclear polarization (DNP) to overcome the sensitivity limitation of conventional solid-state NMR and gain insight into the surface chemistry of drug-functionalized TEMPO-oxidized cellulose nanofibrils. The DNP enhanced-NMR data can report unambiguously on the presence of trace amounts of TEMPO moieties and depolymerized cellulosic units in the starting material, as well as coupling agents on the CNFs surface (used in the heterogeneous reaction). This enables a precise estimation of the drug loading while differentiating adsorption from covalent bonding (∼1 wt% in our case) as opposed to other analytical techniques such as elemental analysis and conductometric titration that can neither detect the presence of coupling agents, nor differentiate unambiguously between adsorption and grafting. The approach, which does not rely on the use of 13C/15N enriched compounds, will be key to further develop efficient surface chemistry routes and has direct implication for the development of drug delivery applications both in terms of safety and dosage., DNP-enhanced solid-state NMR unravels the surface chemistry of functionalized nanocellulose.

Nowadays, drug encapsulation and drug release from cellulose nanofibrils systems are intense research topics, and commercial grades of cellulose nanomaterials are currently available. In this work we present an ester-containing prodrug of metronidazole that is covalently bound to cellulose nanofibrils in aqueous suspension through a two-step immobilization procedure involving green chemistr y principles. The presence of the drug is confirmed by several characterization tools and methods such as Raman spectroscopy, elemental analysis, Dy-namic Nuclear Polarization enhanced NM R . This technique allow s enhancing the sensitivity of NM R by several orders of magnitude. It has been used to study cellulose nanofibrils substrates and it appears as the ultimate tool to confirm the covalent nature of the binding through thiol-yne click chemistry. Moreover, the ester function of the immobilized prodrug can be cleaved by specific enzyme activity thus allowing controlled drug release.

International audience

The π-extended ligand of a ruthenium complex stores two photo-generated electrons, mimicking a key step in photosynthesis., Increasing the efficiency of molecular artificial photosynthetic systems is mandatory for the construction of functional devices for solar fuel production. Decoupling the light-induced charge separation steps from the catalytic process is a promising strategy, which can be achieved thanks to the introduction of suitable electron relay units performing charge accumulation. We report here on a novel ruthenium tris-diimine complex able to temporarily store two electrons on a fused dipyridophenazine–pyridoquinolinone π-extended ligand upon visible-light irradiation in the presence of a sacrificial electron donor. Full characterization of this compound and of its singly and doubly reduced derivatives thanks to resonance Raman, EPR and (TD)DFT studies allowed us to localize the two electron-storage sites and to relate charge photoaccumulation with proton-coupled electron transfer processes.

International audience; We describe the design and optimization of polyfunctional scaffolds based on a fluorescent indolizine core derivatized with various orthogonal groups (amines, esters, oximes, alkynes, etc.). To show one application as tools in biology, the scaffold was used to prepare drug-biotin conjugates that were then immobilized onto avidin-agarose for affinity chromatography. More specifically, the antiangiogenic drug COB223, whose mechanism of action remained unclear, was chosen as a proof-of-concept drug. The drug-selective discrimination of proteins observed after elution of the cell lysates through the affinity columns, functionalized either with the biologically active COB223 or a structurally related inactive analogue (COB236), is a clear indication that the presence of the indolizine core does not limit drug-protein interaction and confirms the usefulness of the indolizine scaffold. Furthermore, the separation of COB223-interacting proteins from human placental extracts unveiled unanticipated protein targets belonging to the family of regulatory RNA-binding proteins, which opens the way to new hypotheses on the mode of action of this antiangiogenic drug.

Aminoglycosides are antibiotic drugs that act through binding to rRNA. In the search for antimicrobial amphiphilic aminoglycosides targeting bacterial membranes, we report here on the discovery of three dialkyl derivatives of the small aminoglycoside neamine active against susceptible and resistant Gram-positive and Gram-negative bacteria. One of these derivatives (R = 2-naphthylpropyl), which has good activity against MRSA and VRSA, showed a low toxicity in eukaryotic cells at 10 μM. The synthesis of amphiphilic paromamine and neamine homologous derivatives pointed out the role of the 6'-amine function of the neamine core in the antibacterial effects. The optimal number of lipophilic substituents to be attached to the neamine core and the corresponding required lipophilicity determined here should permit a more selective targeting of bacterial membranes relative to eukaryotic membranes. This work revealed the existence of windows of lipophilicity necessary for obtaining strong antibacterial effects that should be of interest in the field of antibacterial amphiphilic aminoglycosides.

The lipase-catalysed reaction of aliphatic amine with ethyl propiolate was investigated using benzylamine as reference amine. The conditions were optimised to favour the 1,2-addition, i.e., formation of N-benzylprop-2-ynamide, versus the 1,4-addition. Immobilised Candida antarctica lipase (CALB) was found to be the most efficient enzyme, and the reactions were performed in solvents, such as tBME, dioxane or toluene. The methods were used to prepare propiolamides from aliphatic amines in good to excellent yields. The reactivity of O- and S-nucleophiles was compared in the same conditions.

International audience; The preparation and characterization of three series of novel ruthenium(ii) complexes are reported, each series differing by the nature of the ancillary ligands (2,2'-bipyridine - bpy, 1,10-phenanthroline - phen or 1,4,5,8-tetraazaphenanthrene - TAP). The third ligand was either the heptacyclic heterocycle dipyrido[3,2-a:2',3'-c]quinolino[3,2-h]phenazine (dpqp) substituted at position 12 by an hydroxyl (oxo), 2,2-dimethoxyethylamine (DMEA) or halogeno (Cl or Br) substituent, or the octacyclic dipyrido[3,2-a:2',3'-c]pyrido[2,3,4-de]quinolino[3,2-h]phenazine (dppqp), prepared by a multi-step "chemistry on the complex" strategy from [RuL2(oxo-dpqp)](PF6)2. The three steps, halogenation, substitution by a dimethoxyethylamino group and cyclization in trifluoroacetic acid, were performed in reasonable to high yields depending on the nature of the ancillary ligands. Isolation and purification processes were facilitated by the ability to switch the solubility of the complex from aqueous to organic solvents, depending on the counter-ion. All new complexes were fully characterized; in particular their absorption properties were compared by UV-vis spectroscopy. Finally, π-stacking properties induced by these extended ligands were studied by 1H NMR studies and quantum chemical calculations.

Major increases of the selectivity and/or reactivity in aminosugar and sugar O-alkylation were observed in the presence of tetrabutylammonium fluoride (TBAF) in comparison to TBAI under phase-transfer conditions or in solution. The presence of TBAF allowed the selective and rapid alkylation of the 6-hydroxyl function of neamine and efficient preparation of protected intermediates useful in synthesis and potent or potential antimicrobial O-alkylated derivatives of neamine and paromamine. In regard to the observed strong effects of TBAF, the alkylation and acylation of carbohydrates merit to be studied in the presence of TBAF under phase-transfer conditions.

In this paper, a new ligand-exchange -MEKC mode, based on the design of a unique lipohilic species (4'-octadecylneamine derivative), which served both as micelle-forming surfactant (by its hydrophobic part) and central ion-complexing ligand (by its hydrophilic part) is described. The CMC of the used lipophilic neamine derivative was first determined by surface tension measurements. Subsequent NMR experiments were performed in order to investigate the Cu(II) binding properties of the neamine micellar phase. The enantioseparation properties of both the octadecylneamine derivative-Cu(II) MEKC and the native neamine-Cu(II) CE systems were evaluated and compared using the tryptophan racemate as a probe analyte. The effects of several different electrophoretic conditions on the enantiomer migration behavior in the ligand-exchange-MEKC mode were examined. The developed methodology was also applied to the enantioseparation of other analytes such as 1-methyl-tryptophan, 3,5-diiodo-tyrosine and 1-naphtyl-alanine.

International audience

5-Substituted pyrrolidinones 5 were synthesized in good yields and with fair to good diastereoselectivities from the chiral non-racemic oxazolopyrrolidinone 4 . Various nucleophiles including cuprates, silanes and phosphites were used. The chiral induction is thought to arise from a chelated N -acyliminium species.

3-Alkyl pyrrolidones 9 were synthesized in good yield and high diastereoselectivity by α-alkylation of the new chiral non-racemic lactam 8 derived from ( R )-(−)-phenylglycinol. After debenzylation and introduction of an electron-withdrawing group, 3-methylpyrrolidone 10 is easily hydrolyzed in a basic medium to produce γ-aminobutyric acid (GABA) analogue 13 .

A new access to enantiopure 4,5-disubstituted pyrrolidin-2-ones has been developed from chiral non racemic α,β-unsaturated-γ-lactams. Conjugate addition of Gilman-type cuprates results in trans addition with excellent diastereoselectivity.

2,5-dimethoxy-2,5-dihydrofuran has been used as a synthetic equivalent of 3-formyl propionate in the Pictet-Spengler type reaction of 2-aryl ethylamines to provide the corresponding arylindolizidinones in moderate yields.

Muricatacin is a hydroxy butanolide extracted from Annona muricata, and has shown cytotoxic activity. The threo and erythro aza-analogues, namely the hydroxy pyrrolidones have been synthesized through two different routes.

Starting from O -protected ( R )-(−)-phenylglycinol, chiral silyloxypyrrole 5 was prepared in two steps and its reaction with achiral aldehydes under Mukaiyama's reaction conditions was investigated. Addition occurred at the C-5 position of the pyrrolidine ring with complete lk selectivity (except in the case of acetaldehyde) and a modarate to good diastereofacial ( RR vs SS ) selectivity.

2 I - O - p -Tolylsulfonylcyclomaltoheptaose was obtained in 42% yield by reaction of 1-( p -tolylsulfonyl)-(1 H )-1,2,4-triazole on NaH-deprotonated cyclomaltoheptaose in DMF and further converted into the corresponding mono-2 I ,3 I - manno -epoxide.

The present review focuses on the synthesis and biological evaluation of polycyclic 4(3H)-quinazolinones containing fused aromatic or heteroaromatic rings. The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core. Most of the quinazolinone alkaloids belong to this class of molecules. The second part presents molecules bearing extra ring(s) fused to the benzo moiety of the quinazolinone skeleton. Their structural diversity opens new fields in the search of active molecules.

International audience; The 6-aminoglucosamine ring of the aminoglycoside antibiotic neomycin B (ring II) was conjugated to a 16-mer peptide nucleic acid (PNA) targeting HIV-I TAR RNA. For this purpose, we prepared the aminoglucosamine monomer 15 and attached it to the protected PNA prior to its cleavage from the solid support. We found that the resulting PNA aminoglucosamine conjugate is stable under acidic conditions, efficiently taken up by the human cells and fairly distributed in both cytosol and nucleus without endosomal entrapment because cotreatment with endosome-disrupting agent had no effect on its cellular distribution. The conjugate displayed very high target specificity in vitro and strongly inhibited Tat mediated transactivation of HIV-1 LTR transcription in a cell culture system. The unique properties of this new class of PNA conjugate suggest it to be a potential candidate for therapeutic application.

A new chiral non-racemic γ-lactam 1 easily prepared in one step from ( R )-(−)-phenylglycinol was bis-alkylated α to the carbonyl function in very high to complete diastereoselectivity. The stereochemistry at the so-formed chiral quaternary center was ascertained through an X-ray crystallographic study.

A new chiral non-racemic γ-lactam 1 easily prepared in one step from ( R )-(−)-phenylglycinol was bis-alkylated α to the carbonyl function in very high to complete diastereoselectivity. The stereochemistry at the so-formed chiral quaternary center was ascertained through an X-ray crystallographic study.

Starting from O -protected ( R )-(−)-phenylglycinol, chiral silyloxypyrrole 5 was prepared in two steps and its reaction with achiral aldehydes under Mukaiyama's reaction conditions was investigated. Addition occurred at the C-5 position of the pyrrolidine ring with complete lk selectivity (except in the case of acetaldehyde) and a modarate to good diastereofacial ( RR vs SS ) selectivity.

2,5-dimethoxy-2,5-dihydrofuran has been used as a synthetic equivalent of 3-formyl propionate in the Pictet-Spengler type reaction of 2-aryl ethylamines to provide the corresponding arylindolizidinones in moderate yields.

Muricatacin is a hydroxy butanolide extracted from Annona muricata, and has shown cytotoxic activity. The threo and erythro aza-analogues, namely the hydroxy pyrrolidones have been synthesized through two different routes.

A new access to enantiopure 4,5-disubstituted pyrrolidin-2-ones has been developed from chiral non racemic α,β-unsaturated-γ-lactams. Conjugate addition of Gilman-type cuprates results in trans addition with excellent diastereoselectivity.

5-Substituted pyrrolidinones 5 were synthesized in good yields and with fair to good diastereoselectivities from the chiral non-racemic oxazolopyrrolidinone 4 . Various nucleophiles including cuprates, silanes and phosphites were used. The chiral induction is thought to arise from a chelated N -acyliminium species.

International audience; The aminoglycoside antibiotics bind to the 16S bacterial rRNA and disturb the protein synthesis. One to four hydroxyl functions of the small aminoglycoside neamine were capped with phenyl, naphthyl, pyridyl, or quinolyl rings. The 3',4'- (6), 3',6- (7a), and the 3',4',6- (10a) 2-naphthylmethylene derivatives appeared to be active against sensitive and resistant Staphylococcus aureus strains. 10a also showed marked antibacterial activities against Gram (-) bacteria, including strains expressing enzymes modifying aminoglycosides, efflux pumps, or rRNA methylases. 7a and 10a revealed a weak and aspecific binding to a model bacterial 16S rRNA. Moreover, as compared to neomycin B, 10a showed a lower ability to decrease (3)H leucine incorporation into proteins in Pseudomonas aeruginosa. All together, our results suggest that the 3',4',6-tri-2-naphthylmethylene neamine derivative 10a should act against Gram (-) bacteria through a mechanism different from inhibition of protein synthesis, probably by membrane destabilization.

With the view to develop novel bioinspired nonviral vectors for gene delivery, we synthesized a series of cationic lipids with a neamine headgroup, which incorporates rings I and II of the natural antibiotic aminoglycoside neomycin B. Indeed, we reasoned that neamine might constitute a straightforward and versatile building block for synthesizing a variety of lipophilic aminoglycosides and modulating their characteristics such as size, topology, lipophilicity, number of charges, and charge density. Neamine derivatives bearing long dialkyl chains, one or two neamine headgroups, and four to ten protonatable amine functions were prepared through the selective alkylation of the 4'- or 5-hydroxyl function in ring I and ring II of neamine, respectively. The transfection activity of the twelve derivatives synthesized was investigated in vitro in gene transfection experiments using several mammalian cell lines. The results allowed us to unveil interesting structure-activity relationships and to identify a formulation incorporating a small neamine derivative as a highly efficient gene delivery system.

In this paper, we describe the preparation and the evaluation of a porous graphitic carbon (PGC) column coated with a new dinaphthyl derivative of neamine for chiral ligand-exchange (LE) chromatography. It was shown that the graphitic surface/dinaphthyl anchor system efficiently (1.15 micromol/m(2)) and stably (three months of intensive use) adsorbs the neamine template onto the chromatographic support. The resulting coated PGC stationary phase showed appreciable LE-based enantioselective properties towards several native amino acids.

In this paper, a new class of ligand-exchange chiral stationary phase (LE-CSP) based on the copper complexes of lipophilic aminoglycoside derivatives was reported. Different stationary phases were developed by coating reversed-phase liquid chromatography supports with three neamine derivatives carrying a lipophilic octadecyl chain at the 4', 5 and 6 positions, respectively. The enantioselective ability of these LE neamine-based CSPs was evaluated and the 4'-derivative coated column was found to be the most interesting one for the amino acid resolution. The effects of the variation of several chromatographic parameters on the enantioseparation were evaluated in order to identify the analysis optimal conditions.

In earlier studies, we found that a conjugate of neamine-polyamide nucleic acid targeting transactivation response element of HIV-1 RNA genome (HIV-1 TAR) displayed anti-HIV-1 activity and sequence-specific cleavage of the target RNA in vitro. Here we show that both the position of conjugation of polyamide nucleic acid (PNA) on neamine and the length of the spacer are critical parameters for conferring cleavage activity to the conjugate. The conjugation of PNA via a spacer incorporating 11 atoms to the 5-position of ring I of the neamine core conferred sequence-specific RNA cleavage activity on the conjugate, while conjugation to the 4'-position of ring II abolished this activity. Similarly, 5-neamine PNA complementary to TAR sequence of HIV-1 genome (PNA(TAR)) conjugates having either a 23-atom spacer or a bulky dansyl group between PNA and the neamine core also resulted in complete loss of cleavage activity. Based on these observations, we propose a mechanism for the observed RNA cleavage catalyzed by the conjugate involving unprotonated and protonated amino groups at the 3-position of ring I and the 6'-position of ring II of the neamine core, respectively.

The development of highly enantioselective assays and sensors has received much attention for the determination of enantiomeric impurities at a low level. For chiral compounds, the efficient monitoring of the in selection procedure has allowed the isolation of nucleic acid aptamers which are able to strongly discriminate the target enantiomers. In this paper, we demonstrated for the first time that an aptamer can be successfully used to design a highly enantioselective tool for the trace enantiomer detection. The aptamer-based stereoselective assay was developed using an affinity capillary electrophoresis-based competitive, homogeneous format and an on-capillary mixing approach. Detection of as low as 0.01% of the minor enantiomer in a nonracemic mixture can be achieved, in a short analysis time (

International audience; Various chiral α,β-unsaturated γ-lactams 1 were prepared in high yield and in a single step from corresponding primary amines. The different reactivities of lactams 1 could be exploited to prepare diversely substituted pyrrolidones, pyrrolidines, γ-aminoacids and alkaloids. Their application to the synthesis of enantiomerically pure (-)-cephalotaxine are described.

Dendritic beta-cyclodextrin (betaCD) derivatives bearing multivalent mannosyl ligands have been prepared and assessed for their binding efficiency toward the tetrameric plant lectin concanavalin A (Con A) and a mammalian mannose/fucose specific cell surface receptor from macrophages. The synthetic strategy exploits the reactivity between isothiocyanate and amine functionalities for the high-yielding assembly via thioureido links of the various building blocks, including host, spacer, branching, and carbohydrate ligand elements. The methodology has been applied to the preparation of a series of betaCD-polymannoside scaffolds differing in the ligand valency and geometry. This series allowed us to explore: (i) The effects of the glycodendritic architecture on the binding efficiency; (ii) the mutual influence between the cyclodextrin core and the glycodendritic moieties on the molecular inclusion and lectin-binding properties; and (iii) the consequence of inclusion complex formation, using the anticancer drug docetaxel (Taxotere) as a target guest, on biological recognition. Our results confirm the high drug solubilization capability of this new type of betaCD-dendrimer construct and indicate that subtle changes in the architecture of the conjugate may have important consequences on receptor affinity. Interestingly, the host-guest interaction can be monitored to build up supramolecular dynamic glycoclusters with increased lectin affinity. Alternatively, the information obtained from the structure-lectin-binding avidity-inclusion capability studies has been put forward in the design of very efficient molecular transporters for docetaxel based on glycodendritic CD dimers.

Targeted drug delivery systems have been built from β-cyclodextrin by monoconjugation with mannosyl-coated dendritic branches following an iterative thiourea-forming convergent strategy; the multivalent adducts showed high Concanavalin A lectin binding ability and intact inclusion capabilities.

Targeted drug delivery systems have been built from β-cyclodextrin by monoconjugation with mannosyl-coated dendritic branches following an iterative thiourea-forming convergent strategy; the multivalent adducts showed high Concanavalin A lectin binding ability and intact inclusion capabilities.

International audience; Aminoglycosides are among the most potent antimicrobials to eradicate Pseudomonas aeruginosa. However, the emergence of resistance has clearly led to a shortage of treatment options, especially for critically ill patients. In the search for new antibiotics, we have synthesized derivatives of the small aminoglycoside, neamine. The amphiphilic aminoglycoside 3',4',6-tri-2-naphtylmethylene neamine (3',4',6-tri-2NM neamine) has appeared to be active against sensitive and resistant P. aeruginosa strains as well as Staphylococcus aureus strains (Baussanne et al., 2010). To understand the molecular mechanism involved, we determined the ability of 3',4',6-tri-2NM neamine to alter the protein synthesis and to interact with the bacterial membranes of P. aeruginosa or models mimicking these membranes. Using atomic force microscopy, we observed a decrease of P. aeruginosa cell thickness. In models of bacterial lipid membranes, we showed a lipid membrane permeabilization in agreement with the deep insertion of 3',4',6-tri-2NM neamine within lipid bilayer as predicted by modeling. This new amphiphilic aminoglycoside bound to lipopolysaccharides and induced P. aeruginosa membrane depolarization. All these effects were compared to those obtained with neamine, the disubstituted neamine derivative (3',6-di-2NM neamine), conventional aminoglycosides (neomycin B and gentamicin) as well as to compounds acting on lipid bilayers like colistin and chlorhexidine. All together, the data showed that naphthylmethyl neamine derivatives target the membrane of P. aeruginosa. This should offer promising prospects in the search for new antibacterials against drug- or biocide-resistant strains.

In regard to the antibacterial activity of amphiphilic aminoglycosides which are (i) 3',4',6-trinaphtylmethyl (2NM) et -trihexyl neamine derivatives active against wild-type and resistant to antibiotic drugs Gram (+) et Gram (–) bacteria, and (ii) 3',4'- and 3',6-di2NM derivatives active against bacteria Gram (+) bacteria, the works were focused on the search for more active and less toxic derivatives than the trialkyl derivatives. With this aim, two approaches were developed for obtaining antibacterial amphiphilic aminoglycosides: (1) the synthesis from neomycin B of new neamine derivatives carrying alkyl groups of various lipophily in order to decrease the global lipophily and (2) after the first results in the neamine series, the synthesis from N-acetylglucosamine of amphiphilic derivatives of the aminosugar part of the neamine core named neosamine.In the first approach, after optimisation of alkylation methods of neamine, we shifted from active 3',4',6-trialkylated derivatives to less lipophilic more active and less cytotoxic dialkylated derivatives, especially 3',6 derivatives. In the second approach, from 1-allyl 3,4-dinonyl neosamine, large spectrum antibacterial derivatives carrying at the anomeric position polar groups were obtained through epoxidation of the allylic double bond. Previously, the tri2NM neamine derivative has appeared to be able to strongly bind to the lipopolysaccharides of the outer membrane of P. aeruginosa and to destabilize membranes. The study of the mechanism of action of the most active derivatives prepared suggested a similar mode of action., Après la mise en évidence de la forte activité antibactérienne à large spectre contre des bactéries Gram (+) et Gram (-) sauvages et résistantes aux antibiotiques des dérivés 3',4',6-tri-naphtylméthyl (2NM) et -trihexyl d'un petit aminoglycoside, la néamine, et de l'activité, contre les bactéries Gram (+) sauvages et résistantes, des 3',4'- et 3',6-di2NM néamines, les travaux réalisés ont cherché à obtenir des dérivés antibactériens plus actifs et moins toxiques que les dérivés trialkylés. Deux approches en séries aminoglycosides amphiphiles ont été développées dans ce but : (1) la synthèse à partir de la néomycine B de nouveaux dérivés de la néamine portant des groupements alkyles de différentes lipophilies de façon à diminuer globalement celle-ci et (2) après les premiers résultats en série néamine, la synthèse à partir de la N-acétyl glucosamine de dérivés amphiphiles d'un des constituants de la néamine, la néosamine.Dans la première approche, après la mise au point de méthodes d'alkylation de la néamine, il a été possible de passer de dérivés trialkylés de la néamine à des dérivés dialkylés, en particulier 3',6- dialkylés, plus actifs et moins cytotoxiques ceci en diminuant la lipophilie globale des composés. Dans la deuxième approche, à partir de la 1-allyl 3,4-dinonyl néosamine, des dérivés amphiphiles antibactériens à large spectre portant en position anomérique des groupements polaires ont été préparés après époxydation de la double liaison. Le dérivé tri2NM de la néamine s'était avéré avoir une forte affinité pour les lipopolysaccharides de la membrane externe de P. aeruginosa et agir à travers son caractère amphiphiles pour dépolariser la membrane bactérienne. L'étude du mode d'action des dérivés de la néamine préparés les plus actifs a suggéré un mécanisme d'action similaire.