Enantio- and regioselective CpRu-catalyzed Carroll rearrangement

The addition of unstabilized carbonyl nucleophiles to allyl-metal fragments still represents a challenge for generating stereoselectively tertiary (and quaternary) stereogenic centers. In this context, the decarboxylative Carroll rearrangement of secondary and tertiary allyl β-ketoesters is particularly interesting since chiral γ,δ-unsaturated ketones are obtained. Herein, we show that CpRu half-sandwich complexes can, in the presence of selected enantiopure diimine ligands, catalyze this transformation and afford complete conversions and decent level of enantiomeric excess. Zwitterionic adducts of a hexacoordinated phosphorus anion and CpRu moieties were also associated and shown to generate air-, moisture-, and microwave-stable catalysts that can be readily purified and recycled. Carroll rearrangements of allylic β-ketoesters performed with these zwitterionic species occur with better regio- and enantioselectivit

Synthetic Route to Rare Isoindolones Derivatives

International audienceA shorter and more versatile synthetic route has been developed to prepare tetrahydropyrido[2,1‐a]isoindolone and superior analogues. The key step of this synthesis is the formation of the lactam ring by a cyclization using Shibasaki's conditions.The isoindolone scaffold is present in many biologically active compounds. Here, we have developed a shorter and more efficient synthesis of tetrahydropyrido[2,1‐a]isoindolone. The key step of this approach is a cyclization to form the γ‐lactam ring under Shibasaki's conditions. Thus, tetrahydropyrido[2,1‐a]isoindolone and superior analogues, namely hexahydroazepino[2,1‐a]isoindolone and hexahydroazocino[2,1‐a]isoindolone, have been prepared in only three steps in 39, 25, and 19 % overall yields, respectively. This novel strategy offers a shorter alternative to existing procedures

New nitric oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold: Design, synthesis, in silico and in vitro studies

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Toward an Innovative Treatment of Alzheimer’s Disease: Design of MTDLs Targeting Acetylcholinesterase and α-7 Nicotinic Receptors

International audienceAlzheimer’s disease (AD) is a complex and progressive neurodegenerative disorder. The available therapy is limited to symptomatic treatment, and its efficacy remains unsatisfactory. In view of the prevalence and expected increase in the incidence of AD, the development of an effective therapy is crucial for public health. Since the therapeutic paradigm “one compound–one-target” has shown its limits in the treatment of AD, new strategies are emerging to overcome the lack of efficiency of the current pharmacotherapy in the past decade. The most promising is the multitarget-directed ligands (MTDLs) strategy. This project consists of the development of new multifunctional agents, which will act simultaneously on the different players in AD pathology by combining an AChE inhibitory activity based on the structures of a well-known AChE inhibitor (Rivastigmine) with an α-7 nAChR activation. Indeed, nAChRs were recently put forward as potential targets for the treatment of central nervous system (CNS) diseases, such as AD. Because of their distribution and abundance in the CNS, the α-7 subtypes are potential therapeutic targets for this disorder

PYRIDO[3,2-D]PYRIMIDINES TRISUBSTITUÉES, LEURS PROCÉDÉS DE PRÉPARATION ET LEURS UTILISATIONS EN THÉRAPEUTIQUE

The present invention concerns compounds of the following general formula (I): - R1 is, in particular, an -NRaRb group, Ra and Rb forming, together with the nitrogen atom to which they are bonded, a heterocycle comprising 5 to 30 atoms, - R2 is, in particular, an aryl comprising 5 to 30 atoms, and - R3 is, in particular, an alkenyl comprising 1 to 20 carbon atoms.La présente invention concerne des composés de formule générale (I) suivante : - R1 est notamment un groupe -NRaRb, Ra et Rb formant ensemble avec l'atome d'azote sur lequel ils sont reliés, un hétérocycle comprenant de 5 à 30 atomes, - R2 est notamment un aryle comprenant de 5 à 30 atomes, et - R3 est notamment un alcényle comprenant de 1 à 20 atomes de carbone

Synthesis of novel series of 3,5-disubstituted imidazo[1,2- \textitd ] [1,2,4]thiadiazoles involving S _\textrmN Ar and Suzuki–Miyaura cross-coupling reactions

A convenient design of 3,5-disubstituted imidazo[1,2- d ][1,2,4]thiadiazoles is reported from 2-mercaptoimidazole, which afforded a versatile platform that was then used to access a variety of original heterocycles. , The first access to 3,5-disubstituted imidazo[1,2- d ][1,2,4]thiadiazole derivatives is reported. The series were generated from 2-mercaptoimidazole, which afforded the key intermediate bearing two functional positions. The S N Ar reactivity toward tosyl release at the C-3 position was investigated and a regioselective electrophilic iodination in C-5 position was performed to allow a novel C–C bond using Suzuki–Miyaura reaction. Palladium-catalyzed cross-coupling conditions were optimized. A representative library of various boronic acids was employed to establish the scope and limitations of the method. To complete this methodological study, the influence of the nature of the C-3 imidazo[1,2- d ][1,2,4]thiadiazole substitutions on the arylation in C-5 was investigated

Synthesis and biological evaluation of 2,3-bis(het)aryl-4-azaindole derivatives as protein kinase inhibitors

International audienc

Longitudinal PET Imaging of α7 Nicotinic Acetylcholine Receptors with [18F]ASEM in a Rat Model of Parkinson’s Disease

International audienc

Optimization of the Synthesis of Diclofenac Derivatives with Hydrazone Structure and In Vitro Evaluation of the Anti-Inflammatory Potential

International audienceThe aim of the study was to optimize the synthesis of diclofenac derivative with hydrazones structure in order to obtain higher yields and purity by variation of different parameters such as: ratio between reactants, solvent, catalyst, temperature, time of reaction and method used. The anti-inflammatory effects of diclofenac derivatives were evaluated using in vitro assays: albumin denaturation and erythrocyte membrane stability. The obtained results showed that the effect of the tested derivatives is increasing with the concentration, the best results being obtained at the concentration of 125 �g/mL (albumin denaturation assay), respectively 111.11 �g/mL (erythrocyte membrane stability assay). The most active compound was 4d which showed the highest inhibition effect on albumin denaturation and an appreciable effect on erythrocyte membrane stability, in comparation with diclofenac, used as drug reference

Design, Synthesis, In Silico and In Vitro Studies for New Nitric Oxide-Releasing Indomethacin Derivatives with 1,3,4-Oxadiazole-2-thiol Scaffold

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a–p) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Moreover, their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was also performed. Based on docking results, 8k, 8l and 8m proved to be the best interaction for the COX-2 (cyclooxygense-2) target site, with an improved docking score compared with celecoxib. Referring to the thermal denaturation of serum proteins and antioxidant effects, all the tested compounds were more active than IND and aspirin, used as references. In addition, the compounds 8c, 8h, 8i, 8m, 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects