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Cross-coupling reaction of alkyl and aryl magnesium halides with 4-chloro-pyrrolo-[3,2-c]quinoline in the presence of a catalytic amount of iron salt is described. The reactions are completed in 30 min, resulting in moderate to excellent yields of 52–94% in a tetrahydrofuran (THF)–N-methylpyrrolidinone (NMP) solvent mixture.

DD-ligases catalyze the synthesis of the D-Ala-D-Ala and D-Ala-D-Ser dipeptides or the D Ala-D-Lac depsipeptide in an early step of peptidoglycan synthesis. Their function is essential for bacterial growth and specific to bacteria, making them attractive targets for the development of novel antibiotics. This review examines the biochemical and structural features of these enzymes and presents the main families of inhibitors described so far. Over the last 20 years, 7 structures of DD-ligases have been solved by X-ray crystallography, giving a detailed view of the general topology of the active site and of the residues in the catalytic pocket that play a central role in substrate recognition. This has paved the way to the rational design of inhibitors, which can be classified as (i) analogues of substrates, (ii) analogues of the product of the reaction, (iii) analogues of the transition state, and (iv) original scaffolds discovered by screening or by rational computer-aided design. The three first strategies have led to molecules that are polar by nature and have therefore poor access to their cytosolic target. The fourth one is potentially most promising as it yields more diverse structures. The most active molecules show affinity constants in the microM range, but microbiological evaluation remains scarce (typical MIC 1-8 mg/L for the tested compounds). These data strongly suggest targeting DD-ligases is a promising approach for discovery of new antibiotics. Future research should, however, aim at finding more potent inhibitors endowed with the appropriate pharmacokinetic properties that ensure access to their intracellular target.

International audience; D-Alanyl – D-alanine ligase is an enzyme which catalyzes the dimerization of D-alanine, and, as such, has an essential role in bacterial cell wall biosynthesis. It has been shown that inhibition of D-alanyl – D-alanine ligase prevents bacterial growth. D-Alanyl – D-alanine ligase represents therefore a viable antimicrobial target. The 3D structure of this enzyme complexed with a phosphinophosphate inhibitor has been reported, which allows for structure-based design studies. Four softwares (LUDI, MCSS, Autodock, and Glide) developed either for fragment or full-molecule docking were compared and scored for their ability to position in the active site four prototypic ligands: two inhibitors, i.e. a phosphinophosphate derivative and D-cycloserine, D-alanine and D-alanyl – D-alanine. Best performances were obtained with Glide and MCSS. A short series of novel derivatives based on a 2-phenylbenzoxazole scaffold was designed de novo on the basis of computational data. The best compound was found to fully inhibit the D-alanyl – D-alanine ligase of E. faecalis with an IC50 of 400 mM.

International audience; Cross-coupling reaction of alkyl and aryl magnesium halides with 4-chloro-pyrrolo[3,2-c]quinoline in the presence of a catalytic amount of iron salt is described. The reactions are completed in 30 min, resulting in moderate to excellent yields of 52-94% in a tetrahydrofuran (THF)-N-methylpyrrolidinone NMP solvent mixture

International audience; N-Boc-activated sulfahydantoin can be seen as glycine enolate equivalent. It appeared as a convenient starting material for the stereocontrolled preparation of threonine homologues through an alkaline syn aldolization involving a Boc migration. The methdology allowed the one-pot preparation of constrained analogues of polyoxamic

Various C-aryl and C-alkyl-nitrones were synthesized within 0.5–2 h via condensation of an equimolar amount of aldehydes and N-substituted-hydroxylamines under solvent-free conditions in a ball-mill apparatus. Reactions can be performed without the need of excluding air and moisture and yields the expected products with no need for further purification. The study has been complemented by Differential Scanning Calorimetry (DSC) and solid-state 13C MAS nuclear magnetic resonance experiments. We have also studied the temperature profile during the reaction. A comparative study with the corresponding solvent-free microwave activated reaction showed the superiority of the ball-milling method; 31 examples are described, including the synthesis of the anti-aging agent C-phenyl-N-tert-butyl nitrone (PBN) and one of its analogues C-2-pyridyl-N-tert-butylnitrone (2-PyBN

La chimie verte reduit les substances dangereuses et toxiques. Les solvants de reactions, generalement utilises en grande quantite, entrent dans cette categorie de substances dangereuses. Des solvants alternatifs comme l’eau ont ete proposes, mais le meilleur solvant d’un point de vue ecologique reste l’absence de solvant. Dans un procede, l’utilisation de solvants intervient a differents stades : synthese, purification et nettoyage des equipements. Les methodes presentees ici permettent la suppression des solvants dans les voies de synthese chimique.

International audience; A new approach for the synthesis of original substituted pyrrolo[3,2c] quinoline derivatives using microwave-assisted chemistry is described. The use of microwave activation in this synthesis resulted in high yielding and clean steps. The key step for introducing diversity is the animation or the Pd-catalyzed cross-coupling of an imidoyl chloride derivative, obtained in a straightforward manner and in good yield.

International audience; Various C-aryl and C-alkyl-nitrones were synthesized within 0.5-2h via condensation of an equinolear amount of aldehydes and N-substituted-hydroxylamines under solvent free conditions in a ball-mill apparatus. Reactions can be performed without the need of excluding air and moisture and yields the expected products with no need for further purification. The study has been complemented by Differential Scanning Calorimetry (DSC) and solid-state 13C Mass nuclear magnetic resonance experiments. We have also studied the temperature profile during the reaction. A comparative study with the corresponding solvent-free microwave activated reaction showed be superiority of the ball-milling method; 31 examples are described, including the synthesis of the anti-aging agent C-phenyl-N-tert-butyl nitrone (PBN) and one of its analogues C-2-pyridyl-N-tert-butylnitrone (2-PyBN).

International audience; A new and high yielding approach for the synthesis of a novel pyrrolo-[3,2-c]quinoline N-oxide is described. The key step consisted in the palladium-catalyzed reductive cyclization of an uncomon 3-ketopyrrole derivative of o-nitrobenzaldehyde, obtained in a straightforward manner through an aza-Baylis-Hillman/ring closing metathesis/aromatization reaction. A deoxygenation reaction of this novel pyrrolo-[3,2-c]quinoline N-oxide afforded a new substituted pyrrolo-[3,2-c]quinoline analogue.

International audience; A microwave-assisted synthesis of 1,3,5-substituted hydantoins starting from various resins for solid-phase combinatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and the nucleofuge properties of the resin.

The Willgerodt-Kindler reaction was applied to a series of aromatic aldehydes and ketones. The reactions were performed in a dipolar aprotic solvent (mainly DMF) in the presence of a base catalyst (4-methylmorpholine) and utilized microwave (mw) irradiation. The pulsed mw technique rather than the continuous irradiation was preferred because it limited side reactions and hydrogen sulfide production. While not always superior to the thermal activation of the reaction, the procedure involving repetitive short pulses of microwave irradiation was found to be faster and result in consistently cleaner products. The technique can be easily applied in a fast parallel synthesis process.

In this article, we describe the synthesis of 5-nitro-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)cytosine (4alpha), 5-nitro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)cytosine (4beta), 5-amino-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)cytosine (5alpha), 5-nitro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)cytosine (5beta), 5-nitro-1-(2,3-dideoxy-beta-D-ribofuranosyl)uracil (6beta), 5-amino-1-(2,3-dideoxy-alpha,beta-D-ribofuranosyl)uracil (7), 5-nitro-1-(2,3-dideoxy-alpha,beta-D-ribofuranosyl)cytosine (8) and 5-amino-1-(2,3-dideoxy-beta-D-ribofuranosyl)cytosine (9beta). The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant activity.

4'-Aza-2',3'-dideoxyerythrofuranosyl derivatives of thymine (AdT, 1) and uracil (AdU, 2) are analogues of 2',3'-dideoxyribofuranosyl thymine (ddT, 3) and uracyl (ddU, 4). Compounds 1 and 2 are representative of a new class of antiviral agents where the sugar moiety is replaced by an isoxazolidine ring. The increasing importance of isoxazolidinyl nucleosides has encouraged the exploitation of simple mass spectrometric rules for unambiguously assigning their structure. The species 1, 2, 5 and 6 were therefore synthesized in order to evaluate the role of the basic centre of the modified sugar moiety in their gas-phase chemistry. The tandem mass spectra of these compounds are similar to those of the wild-type nucleosides and display fragment ions corresponding to [B + 2H] + , [M - BH] + and [B + 27] + species, where B is the nucleobase. The last species derives from a retrocycloaddition process which is less evident in 2'-deoxyribosides. This behaviour is consistent with protonation of the analytes at the pyrimidine rings. Model isoxazolidines, in which the nucleobase was replaced by a phenyl or a naphthyl moiety, displayed the expected behaviour of species with a localized charge on the N-O moiety of the isoxazolidine ring.

A rapid and convenient large-scale strategy for the synthesis of some new isoxazolidinyl nucleosides, as potential antiviral drugs, is reported. In particular, a multistep methodology based either on the 1,3-dipolar cycloaddition approach or on a slight modification of the convertible nucleoside concept was exploited in the preparation of 4′-aza-2′,3′-dideoxynucleoside analogues containing cytosine and 5-methyl-cytosine.

International audience; Phosphine-free palladium-catalyzed Mizoroki-Heck reaction was performed using ball-milling in polyethylene glycol under mild conditions. Good to excellent yields of coupling products were obtained. This activation technique also allowed the concomitant formation of round shaped Pd-PEG nanoparticles that were characterized by TEM analysis.

The complete set of the 4′-aza analogues of 2′,3′-dideoxynucleosides was synthesized by cycloaddition of N-tetrahydropiranyl or N-trityl methylene nitrones on suitably protected vinyl nucleobases. The convertible nucleoside approach was used in the preparation of cytosine and 5-methyl cytosine analogues.