Publications by authors named "Sylvain Routier"

63 Publications

Prodromal neuroinflammatory, cholinergic and metabolite dysfunction detected by PET and MRS in the TgF344-AD transgenic rat model of AD: a collaborative multi-modal study.

Theranostics 2021 3;11(14):6644-6667. Epub 2021 May 3.

Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK.

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing and mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [F]DPA-714 (TSPO, neuroinflammation), [F]Florbetaben (Aβ) and [F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aβ, NeuN, NeuroChrom) and Tau (S)-[F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. [F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. [F]ASEM PET revealed an age-dependent increase uptake in the striatum and in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. [F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aβ plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aβ plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aβ plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in this model, validated by robust approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.
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http://dx.doi.org/10.7150/thno.56059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171096PMC
May 2021

[ F]-labeled positron emission tomography ligand for the histamine H4 receptor.

J Labelled Comp Radiopharm 2021 Jun 5. Epub 2021 Jun 5.

UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.

We synthesized 5-[ F]-fluoro-1H-indol-2-yl)(4-methyl-1-piperazinyl)methanone ([ F]5) via a Suzuki approach starting from a protected pinacol borane precursor followed by acidic hydrolysis of the t-Boc protecting group. The non-optimized radiochemical yield was 5.7 ± 1.35%, radiochemical purity was over 99%, and molar activity was 100.7 ± 34.5 GBq/μmol (n = 3). [ F]5 was stable in rat plasma for at least 4 h and was evaluated by μPET imaging and biodistribution using a unilateral quinolinic acid rat model of neuroinflammation. The time-activity curve showed that [ F]5 entered the brain immediately after intravenous injection and then left it progressively with a very low level reached from 30 min after injection. The biodistribution study showed no difference in the accumulation of [ F]5 between the lesioned and intact side of the brain and between control rats and animals pretreated with a saturating dose of JNJ-7777120 as a specific H4R antagonist. Hence, despite its in vitro nanomolar affinity for H4R, and its ability to cross the blood-brain barrier in rats, [ F]5 does not appear suitable to image in vivo the receptor by PET.
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http://dx.doi.org/10.1002/jlcr.3929DOI Listing
June 2021

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

Biomed Pharmacother 2021 Jul 6;139:111678. Epub 2021 May 6.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy of Iași, 16 University Street, Iasi, Romania. Electronic address:

In this study we present design and synthesis of nineteen new nitric oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs) (6a-s), as a new safer and efficient multi-targets strategy for inflammatory diseases. The chemical structure of all synthesized derivatives (intermediaries and finals) was proved by NMR and mass spectroscopic analysis. In order to study the selectivity of NO-IND-TZDs for COX isoenzymes (COX-1 and COX-2) a molecular docking study was performed using AutoDock 4.2.6 software. Based on docking results, COX-2 inhibitors were designed and 6o appears as the most selective derivative which showed an improved selective index compared with indomethacin (IND) and diclofenac (DCF), used as reference drugs. The biological evaluation of 6a-s, using in vitro assays has included the anti-inflammatory and antioxidant effects as well as the nitric oxide (NO) release. Referring to the anti-inflammatory effects, the most active compound was 6i, which was more active than IND and aspirin (ASP) in term of denaturation effect, on bovine serum albumin (BSA), as indirect assay to predict the anti-inflammatory effect. An appreciable anti-inflammatory effect, in reference with IND and ASP, was also showed by 6k, 6c, 6q, 6o, 6j, 6d. The antioxidant assay revealed the compound 6n as the most active, being 100 times more active than IND. The compound 6n showed also the most increase capacity to release NO, which means is safer in terms of gastro-intestinal side effects. The ADME-Tox study revealed also that the NO-IND-TZDs are generally proper for oral administration, having optimal physico-chemical and ADME properties. We can conclude that the compounds 6i and 6n are promising agents and could be included in further investigations to study in more detail their pharmaco-toxicological profile.
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http://dx.doi.org/10.1016/j.biopha.2021.111678DOI Listing
July 2021

New ibuprofen derivatives with thiazolidine-4-one scaffold with improved pharmaco-toxicological profile.

BMC Pharmacol Toxicol 2021 02 4;22(1):10. Epub 2021 Feb 4.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, University of Medicine and Pharmacy "Grigore T. Popa" of Iasi, Iași, Romania.

Background: Aryl-propionic acid derivatives with ibuprofen as representative drug are very important for therapy, being recommended especially for anti-inflammatory and analgesic effects. On other hand 1,3-thiazolidine-4-one scaffold is an important heterocycle, which is associated with different biological effects such as anti-inflammatory and analgesic, antioxidant, antiviral, antiproliferative, antimicrobial etc. The present study aimed to evaluated the toxicity degree and the anti-inflammatory and analgesic effects of new 1,3-thiazolidine-4-one derivatives of ibuprofen.

Methods: For evaluation the toxicity degree, cell viability assay using MTT method and acute toxicity assay on rats were applied. The carrageenan-induced paw-edema in rat was used for evaluation of the anti-inflammatory effect while for analgesic effect the tail-flick test, as thermal nociception in rats and the writhing assay, as visceral pain in mice, were used.

Results: The toxicological screening, in terms of cytotoxicity and toxicity degree on mice, revealed that the ibuprofen derivatives (4a-n) are non-cytotoxic at 2 μg/ml. In addition, ibuprofen derivatives reduced carrageenan-induced paw edema in rats, for most of them the maximum effect was recorded at 4 h after administration which means they have medium action latency, similar to that of ibuprofen. Moreover, for compound 4d the effect was higher than that of ibuprofen, even after 24 h of administration. The analgesic effect evaluation highlighted that 4 h showed increased pain inhibition in reference to ibuprofen in thermal (tail-flick assay) and visceral (writhing assay) nociception models.

Conclusions: The study revealed for ibuprofen derivatives, noted as 4 m, 4 k, 4e, 4d, a good anti-inflammatory and analgesic effect and also a safer profile compared with ibuprofen. These findings could suggest the promising potential use of them in the treatment of inflammatory pain conditions.
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http://dx.doi.org/10.1186/s40360-021-00475-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863240PMC
February 2021

Neuroprotective and anti-inflammatory effects of a therapy combining agonists of nicotinic α7 and σ1 receptors in a rat model of Parkinson's disease.

Neural Regen Res 2021 Jun;16(6):1099-1104

UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.

To date there is no treatment able to stop or slow down the loss of dopaminergic neurons that characterizes Parkinson's disease. It was recently observed in a rodent model of Alzheimer's disease that the interaction between the a7 subtype of nicotinic acetylcholine receptor (a7-nAChR) and sigma-1 receptor (s1-R) could exert neuroprotective effects through the modulation of neuroinflammation which is one of the key components of the pathophysiology of Parkinson's disease. In this context, the aim of the present study was to assess the effects of the concomitant administration of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-furo[2,3-c]pyridine-5-carboxamide (PHA) 543613 as an a7-nAChR agonist and 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE)-084 as a s1-R agonist in a well-characterized 6-hydroxydopamine rat model of Parkinson's disease. The animals received either vehicle separately or the dual therapy PHA/PRE once a day until day 14 post-lesion. Although no effect was noticed in the amphetamine-induced rotation test, our data has shown that the PHA/PRE treatment induced partial protection of the dopaminergic neurons (15-20%), assessed by the dopamine transporter density in the striatum and immunoreactive tyrosine hydroxylase in the substantia nigra. Furthermore, this dual therapy reduced the degree of glial activation consecutive to the 6-hydroxydopamine lesion, i.e, the 18 kDa translocation protein density and glial fibrillary acidic protein staining in the striatum, and the CD11b and glial fibrillary acidic protein staining in the substantia nigra. Hence, this study reports for the first time that concomitant activation of a7-nAChR and s1-R can provide a partial recovery of the nigro-striatal dopaminergic neurons through the modulation of microglial activation. The study was approved by the Regional Ethics Committee (CEEA Val de Loire n°19) validated this protocol (Authorization N°00434.02) on May 15, 2014.
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http://dx.doi.org/10.4103/1673-5374.300451DOI Listing
June 2021

Design of new disubstituted imidazo[1,2-]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1840-1853

Sorbonne Université/CNRS UMR8227, Station Biologique, Roscoff cedex, France.

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC between 6 and 100 nM . The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB.
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http://dx.doi.org/10.1080/14756366.2020.1825408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580722PMC
December 2020

Gold(I)-Catalyzed Intramolecular Hydroamination and Hydroalkoxylation of Alkynes: Access to Original Heterospirocycles.

Org Lett 2020 Aug 21;22(15):5973-5977. Epub 2020 Jul 21.

Institut de Chimie Organique et Analytique, Université d'Orléans, CNRS UMR 7311, 45067 Cedex 2, Orléans, France.

We report here a simple and robust gold-catalyzed annulation reaction, giving - and -spirocycles in good to excellent yields. We have prepared a library of protected amines and tertiary alcohols that give, upon cyclization with alkynes, a representative set of heterospirocycles and illustrate reaction compatibility with diverse functional groups. A change in catalytic activity is possible by modifying the solvent, and two original tricyclic spirocycles were synthesized in a tandem reaction.
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http://dx.doi.org/10.1021/acs.orglett.0c02070DOI Listing
August 2020

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

Mol Imaging Biol 2020 04;22(2):348-357

UMR Inserm U1253, iBrain, Université de Tours, UFR de Médecine, 10 Boulevard Tonnellé, 37032, Tours Cedex 01, France.

Purpose: The nicotinic acetylcholine alpha-7 receptors (α7R) are involved in a number of neuropsychiatric and neurodegenerative brain disorders such as Parkinson's disease (PD). However, their specific pathophysiologic roles are still unclear. In this context, we studied the evolution of these receptors in vivo by positron emission tomography (PET) imaging using the recently developed tracer 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[F]fluorodibenzo[b,d]thiophene-5,5-dioxide) in a rat model mimicking early stages of PD.

Procedures: PET imaging of α7R was performed at 3, 7, and 14 days following a partial striatal unilateral lesion with 6-hydroxydopamine in adult rats. After the last imaging experiments, the status of nigro-striatal dopamine neurons as well as different markers of neuroinflammation was evaluated on brain sections by autoradiographic and immunofluorescent experiments.

Results: We showed an early and transitory rise in α7R expression in the lesioned striatum and substantia nigra, followed by over-expression of several gliosis activation markers in these regions of interest.

Conclusions: These findings support a longitudinally follow-up of α7R in animal models of PD and highlight the requirement to use a potential neuroprotective approach through α7R ligands at the early stages of PD.
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http://dx.doi.org/10.1007/s11307-019-01400-yDOI Listing
April 2020

Bis(het)aryl-1,2,3-triazole quinuclidines as α7 nicotinic acetylcholine receptor ligands: Synthesis, structure affinity relationships, agonism activity, [F]-radiolabeling and PET study in rats.

Eur J Med Chem 2019 Oct 27;179:449-469. Epub 2019 Jun 27.

Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, rue de Chartres, BP 6759, 45067, Orleans Cedex 2, France. Electronic address:

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.
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http://dx.doi.org/10.1016/j.ejmech.2019.06.049DOI Listing
October 2019

Preparation, Characterization and Wound Healing Effects of New Membranes Based on Chitosan, Hyaluronic Acid and Arginine Derivatives.

Polymers (Basel) 2018 Jun 2;10(6). Epub 2018 Jun 2.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, 16 University Street, Iasi 700115, Romania.

New membranes based on chitosan and chitosan-hyaluronic acid containing new arginine derivatives with thiazolidine-4-one scaffold have been prepared using the ionic cross-linking method. The presence of the arginine derivatives with thiazolidine-4-one scaffold into the polymer matrix was proved by Fourier-transform infrared spectroscopy (FT-IR). The scanning electron microscopy (SEM) revealed a micro-porous structure that is an important characteristic for the treatment of burns, favoring the exudate absorption, the rate of colonization, the cell structure, and the angiogenesis process. The developed polymeric membranes also showed good swelling degree, improved hydrophilicity, and biocompatibility in terms of surface free energy components, which supports their application for tissue regeneration. Moreover, the chitosan-arginine derivatives (CS-6h, CS-6i) and chitosan-hyaluronic acid-arginine derivative (CS-HA-6h) membranes showed good healing effects on the burn wound model induced to rats. For these membranes a complete reepithelialization was observed after 15 days of the experiment, which supports a faster healing process.
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http://dx.doi.org/10.3390/polym10060607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404145PMC
June 2018

Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3.

Eur J Med Chem 2019 Apr 13;168:58-77. Epub 2019 Feb 13.

Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), 76000, Rouen, France. Electronic address:

Both cholinesterases (AChE and BChE) and kinases, such as GSK-3α/β, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3α/β (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3α/β. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.
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http://dx.doi.org/10.1016/j.ejmech.2018.12.063DOI Listing
April 2019

Formulation and Characterization of New Polymeric Systems Based on Chitosan and Xanthine Derivatives with Thiazolidin-4-One Scaffold.

Materials (Basel) 2019 Feb 13;12(4). Epub 2019 Feb 13.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy "Grigore T. Popa", 16 University Street, 700115 Iasi, Romania.

In the past many research studies have focused on the thiazolidine-4-one scaffold, due to the important biological effects associated with its heterocycle. This scaffold is present in the structure of many synthetic compounds, which showed significant biological effects such as antimicrobial, antifungal, antioxidant, anti-inflammatory, analgesic, antidiabetic effects. It was also identified in natural compounds, such as actithiazic acid, isolated from strains. Starting from this scaffold new xanthine derivatives have been synthetized and evaluated for their antibacterial and antifungal effects. The antibacterial action was investigated against Gram positive ( ATCC 25923, ATCC 9341) and Gram negative ( ATCC 25922) bacterial strains. The antifungal potential was investigated against Candida spp. ( ATCC 10231, ATCC MYA 2950, ATCC 22019). In order to improve the antimicrobial activity, the most active xanthine derivatives with thiazolidine-4-one scaffold (XTDs: 6c, 6e, 6f, 6k) were included in a chitosan based polymeric matrix (CS). The developed polymeric systems (CS-XTDs) were characterized in terms of morphological (aspect, particle size), physic-chemical properties (swelling degree), antibacterial and antifungal activities, toxicity, and biological functions (bioactive compounds loading, entrapment efficiency). The presence of xanthine-thiazolidine-4-one derivatives into the chitosan matrix was confirmed using Fourier transform infrared (FT-IR) analysis. The size of developed polymeric systems, CS-XTDs, ranged between 614 µm and 855 µm, in a dry state. The XTDs were encapsulated into the chitosan matrix with very good loading efficiency, the highest entrapment efficiency being recorded for CS-6k, which ranged between 87.86 ± 1.25% and 93.91 ± 1.41%, depending of the concentration of 6k. The CS-XTDs systems showed an improved antimicrobial effect with respect to the corresponding XTDs. Good results were obtained for CS-6f, for which the effects on ATCC 25923 (21.2 ± 0.43 mm) and ATCC 9341 (25.1 ± 0.28 mm) were comparable with those of ciprofloxacin (25.1 ± 0.08 mm/25.0 ± 0.1 mm), which were used as the control. The CS-6f showed a notable antifungal effect, especially on ATCC 22019 (18.4 ± 0.42 mm), the effect being comparable to those of nystatin (20.1 ± 0.09 mm), used as the control. Based on the obtained results these polymeric systems, consisting of thiazolidine-4-one derivatives loaded with chitosan microparticles, could have important applications in the food field as multifunctional (antimicrobial, antifungal, antioxidant) packaging materials.
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http://dx.doi.org/10.3390/ma12040558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416560PMC
February 2019

Design of selective COX-2 inhibitors in the (aza)indazole series. Chemistry, in vitro studies, radiochemistry and evaluations in rats of a [F] PET tracer.

J Enzyme Inhib Med Chem 2019 Dec;34(1):1-7

a ICOA, UMR CNRS 7311 , University of Orleans , Orleans , France.

A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C-H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC values of 0.409 µM and an excellent selectivity versus COX-1. Radiolabeling of this most potent derivative [F]16 was achieved after boron ester release and the tracer was evaluated in vivo in a rat model of neuroinflammation. All chemistry, radiochemistry and biological experimental data are discussed.
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http://dx.doi.org/10.1080/14756366.2018.1501043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211253PMC
December 2019

Regioselective Synthesis of New 2,4-(Het)aryl-3H-pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidines Involving Palladium-Catalyzed Cross-Coupling Reactions.

Molecules 2018 Oct 23;23(11). Epub 2018 Oct 23.

Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, BP 6759, F-45067 Orléans CEDEX 2, France.

The design of some novel di-(het)arylated-3-pyrido[1',2':1,5]pyrazolo[4,3-]pyrimidine derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium catalyzed cross coupling reactions by alkyl sulfur release and C-O activation, respectively. The two regioselective and successive cross-coupling reactions were first carried out in C-4 by in situ C-O activation and next in C-2 by a methylsulfur release. Process optimization furnished conditions leading to products in high yields. The scope and limitations of the methodologies were evaluated and the final compounds characterized.
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http://dx.doi.org/10.3390/molecules23112740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278517PMC
October 2018

Synthesis of [1,3,4]Thiadiazolo[3',2':1,2]imidazo[4,5-c]quinolines including Pictet-Spengler Reaction and Exploration of Their C-2 Reactivity through SAr.

J Org Chem 2017 12 21;82(24):13700-13707. Epub 2017 Nov 21.

Institut de Chimie Organique et Analytique, ICOA, Univ Orleans , CNRS UMR 7311, Rue de Chartres, BP 6759, 45067 Orleans, France.

This work reports the design of [1,3,4]thiadiazolo[3',2':1,2]imidazo[4,5-c]quinolines using a Pictet-Spengler reaction. The scope of the reaction was achieved from 6-(2-aminophenyl)imidazo[2,1-b][1,3,4]thiadiazole derivatives and available aldehydes. A wide range of aldehydes were employed to examine the scope of the cyclization. In parallel, a mechanism investigation was realized and showed a hydride transfer which led to a dismutation of the intermediate species. To complete this methodological study, a "sequential" oxidation/SAr procedure was performed to achieve C-2 nucleophilic substitution using several amine types.
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http://dx.doi.org/10.1021/acs.joc.7b02565DOI Listing
December 2017

Perinatal Exposure to the Cyanotoxin β-N-Méthylamino-L-Alanine (BMAA) Results in Long-Lasting Behavioral Changes in Offspring-Potential Involvement of DNA Damage and Oxidative Stress.

Neurotox Res 2018 Jan 6;33(1):87-112. Epub 2017 Sep 6.

Neuroinflammation Group, MND and Neurodegenerative Diseases Research Center, Macquarie University, Sydney, NSW, 2109, Australia.

We recently demonstrated that perinatal exposure to the glutamate-related herbicide, glufosinate ammonium, has deleterious effects on neural stem cell (NSC) homeostasis within the sub-ventricular zone (SVZ), probably leading to ASD-like symptoms in offspring later in life. In the present study, we aimed to investigate whether perinatal exposure to another glutamate-related toxicant, the cyanobacterial amino acid β-N-methylamino-L-alanine (BMAA), might also trigger neurodevelopmental disturbances. With this aim, female mice were intranasally exposed to low doses of BMAA, 50 mg kg three times a week from embryonic days 7-10 to postnatal day 21. Behavioral analyses were performed during the offspring's early life and during adulthood. Developmental analyses revealed that perinatal exposure to BMAA hastened the appearance of some reflexes and communicative skills. BMAA-exposed offspring displayed sex-dependent changes in emotional cognition shortly after exposure. Later in life, the female offspring continued to express emotional defects and to display abnormal sociability, while males were less affected. To assess whether early exposure to BMAA had deleterious effects on NSC homeostasis, we exposed mice NSCs to 1 and 3 mM BMAA during 24 h. We found that BMAA-exposed NSCs produced high levels of ROS, highlighting the ability of BMAA to induce oxidative stress. We also showed that BMAA exposure increased the number of γH2AX/53BP1 foci per nucleus, suggesting that BMAA-induced DNA damage in NSCs. Collectively, this data strongly suggests that perinatal exposure to the cyanobacteria BMAA, even at low doses, results in neurobehavioral disturbances during both the postnatal period and adulthood. This is considered to be underpinned at the cellular level through dysregulation of NSC homeostasis in the developing brain.
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http://dx.doi.org/10.1007/s12640-017-9802-1DOI Listing
January 2018

Neuroprotective effect of the alpha 7 nicotinic receptor agonist PHA 543613 in an in vivo excitotoxic adult rat model.

Neuroscience 2017 07 18;356:52-63. Epub 2017 May 18.

UMR INSERM U930, Université François Rabelais, Tours, France; CHRU de Tours, Hôpital Bretonneau, Tours, France. Electronic address:

Neuroinflammation is a key component of the pathophysiology of neurodegenerative diseases. The link between nicotine intake and positive outcome has been established, suggesting a role played by nicotinic receptors (nAChRs), especially α7nAChRs. The objective of this study was to evaluate the potential dose effects of PHA 543613 on neuron survival and striatal microglial activation in a rat model of brain excitotoxicity. A preliminary study was performed in vitro to confirm PHA 543613 agonist properties on α7nAChRs. Rats were lesioned in the right striatum with quinolinic acid (QA) and received either vehicle or PHA 543613 at 6 or 12mg/kg twice a day until sacrifice at Day 4 post-lesion. We first compared the translocator protein quantitative autoradiography in QA-lesioned brains with [H]DPA-714 and [H]PK-11195. The effects of PHA 543613 on microglial activation and neuronal survival were then evaluated through [H]DPA-714 binding and immunofluorescence staining (Ox-42, NeuN) on adjacent brain sections. We demonstrated that [H]DPA-714 provides a better signal-to-noise ratio than [H]PK-11195. Furthermore, we showed that repeated PHA 543613 administration at a dose of 12mg/kg to QA-lesioned rats significantly protected neurons and reduced the intensity of microglial activation. This study reinforces the hypothesis that α7nAChR agonists can provide beneficial effects in the treatment of neurodegenerative diseases through potential modulation of microglial activation.
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http://dx.doi.org/10.1016/j.neuroscience.2017.05.019DOI Listing
July 2017

Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways.

Sci Rep 2017 05 12;7(1):1815. Epub 2017 May 12.

INSERM U991, Liver Metabolisms and Cancer, Rennes, France.

The penicillinase-resistant antibiotics (PRAs), especially the highly prescribed flucloxacillin, caused frequent liver injury via mechanisms that remain largely non-elucidated. We first showed that flucloxacillin, independently of cytotoxicity, could exhibit cholestatic effects in human hepatocytes in the absence of an immune reaction, that were typified by dilatation of bile canaliculi associated with impairment of the Rho-kinase signaling pathway and reduced bile acid efflux. Then, we analyzed the sequential molecular events involved in flucloxacillin-induced cholestasis. A crucial role of HSP27 by inhibiting Rho-kinase activity was demonstrated using siRNA and the specific inhibitor KRIBB3. HSP27 activation was dependent on the PKC/P38 pathway, and led downstream to activation of the PI3K/AKT pathway. Other PRAs induced similar cholestatic effects while non PRAs were ineffective. Our results demonstrate that PRAs can induce cholestatic features in human hepatocytes through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways and consequently support the conclusion that in clinic they can cause a non-immune-mediated cholestasis that is not restricted to patients possessing certain genetic determinants.
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http://dx.doi.org/10.1038/s41598-017-01171-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431934PMC
May 2017

Synthesis and Antiproliferative Effect of Ethyl 4-[4-(4-Substituted Piperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxalinecarboxylate Derivatives on Human Leukemia Cells.

ChemMedChem 2017 06 5;12(12):940-953. Epub 2017 Apr 5.

UFR des Sciences Pharmaceutiques, Univ. Bordeaux, ARNA Laboratory, 33076, Bordeaux cedex, France.

Acute leukemia is a hematological malignancy with high incidence and recurrence rates and is characterized by an accumulation of blasts in bone marrow due to proliferation of immature lymphoid or myeloid cells associated with a blockade of differentiation. The heterogeneity of leukemia led us to look for new specific molecules for leukemia subtypes or for therapy-resistant cases. Among heterocyclic derivatives that attracted attention due to their wide range of biological activities, we focused our interest on the pyrrolo[1,2-a]quinoxaline heterocyclic framework that has been previously identified as an interesting scaffold for antiproliferative activities against various human cancer cell lines. In this work, new ethyl 4-[4-(4-substituted piperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxalinecarboxylate derivatives (1 a-o) were designed, synthesized, and evaluated against five different leukemia cell lines, including Jurkat and U266 (lymphoid cell lines) and K562, U937, and HL60 (myeloid cell lines), as well as on normal human peripheral blood mononuclear cells (PBMCs). This new pyrrolo[1,2-a]quinoxaline series showed interesting cytotoxic potential against all tested leukemia cell lines. In particular, pyrroloquinoxalines 1 a and 1 m,n seem to be interesting due to their high activity against leukemia and their low activity against normal hematopoietic cells, leading to a high index of selectivity.
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http://dx.doi.org/10.1002/cmdc.201700049DOI Listing
June 2017

Synthesis and biological evaluation of the new 1,3-dimethylxanthine derivatives with thiazolidine-4-one scaffold.

Chem Cent J 2017 1;11:12. Epub 2017 Feb 1.

The Department of Pharmaceutical Chemistry, The Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy, No. 16 University Street, Iasi, 700115 Romania.

Background: The xanthine structure has proved to be an important scaffold in the process of developing a wide variety of biologically active molecules such as bronchodilator, hypoglycemiant, anticancer and anti-inflammatory agents. It is known that hyperglycemia generates reactive oxygen species which are involved in the progression of diabetes mellitus and its complications. Therefore, the development of new compounds with antioxidant activity could be an important therapeutic strategy against this metabolic syndrome.

Results: New thiazolidine-4-one derivatives with xanthine structure have been synthetized as potential antidiabetic drugs. The structure of the synthesized compounds was confirmed by using spectral methods (FT-IR, H-NMR, C-NMR, F-NMR, HRMS). Their antioxidant activity was evaluated using in vitro assays: DPPH and ABTS radical scavenging ability and phosphomolybdenum reducing antioxidant power assay. The developed compounds showed improved antioxidant effects in comparison to the parent compound, theophylline. In the case of both series, the intermediate () and final compounds (), the aromatic substitution, especially in position with halogens (fluoro, chloro), methyl and methoxy groups, was associated with an increase of the antioxidant effects.

Conclusions: For several thiazolidine-4-one derivatives the antioxidant effect of was superior to that of their corresponding hydrazone derivatives. The most active compound was which registered the highest radical scavenging activity.Graphical abstractDesign and synthesis of new thiazolidine-4-one derivatives.
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http://dx.doi.org/10.1186/s13065-017-0241-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289128PMC
February 2017

Controlled Dimroth Rearrangement in the Suzuki-Miyaura Cross Coupling of Triazolopyridopyrimidines.

J Org Chem 2016 12 5;81(24):12506-12513. Epub 2016 Dec 5.

Institut de Chimie Organique et Analytique (ICOA) UMR 7311, University of Orléans, CNRS , BP 6759, Orléans F-45067, France.

Polynitrogen heterocycles are often subject to Dimroth rearrangement which consists of ring opening, bond rotation, and ring closure. In this note, we report a synthesis of two new families of triazolopyridopyrimidines. Successful functionalization via a Suzuki-Miyaura coupling was performed with total control of triazole (Dimroth) isomerization based on the judicious choice of reaction conditions.
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http://dx.doi.org/10.1021/acs.joc.6b02357DOI Listing
December 2016

30ièmes Journées Franco-Belges de Pharmacochimie.

Pharmaceuticals (Basel) 2016 Nov 18;9(4). Epub 2016 Nov 18.

Institut de Chimie Organique et Analytique, CNRS UMR 7311, Université d'Orléans, F-45067 Orléans, France.

The "Journées Franco-Belges de Pharmacochimie" is a recognized annual meeting in organic and medicinal chemistry known for the quality of scientific exchange and conviviality. Young researchers were encouraged to present their work and share ideas with senior scientists. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.
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http://dx.doi.org/10.3390/ph9040073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198048PMC
November 2016

Novel optimization of valmerins (tetrahydropyrido[1,2-a]isoindolones) as potent dual CDK5/GSK3 inhibitors.

Eur J Med Chem 2016 Jun 2;115:311-25. Epub 2016 Mar 2.

Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France. Electronic address:

An efficient synthetic strategy able to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton was developed. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally to support the SAR, a docking study was performed. A potent GSK3/CDK5 dual inhibitor (37, IC50 CDK5/GSK3 35/7 nM) was obtained. Best antiproliferative effects were obtained on lung and prostate cell lines with IC50 = 20 nM.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.072DOI Listing
June 2016

Synthesis and evaluation of the cytotoxic activity of novel ethyl 4-[4-(4-substitutedpiperidin-1-yl)]benzyl-phenylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives in myeloid and lymphoid leukemia cell lines.

Eur J Med Chem 2016 May 20;113:214-27. Epub 2016 Feb 20.

Univ. Bordeaux, UFR des Sciences Pharmaceutiques, ARNA Laboratory, F-33076 Bordeaux cedex, France; INSERM U1212, UMR CNRS 5320, ARNA Laboratory, F-33000 Bordeaux, France. Electronic address:

Leukemia is the most common blood cancer, and its development starts at diverse points, leading to distinct subtypes that respond differently to therapy. This heterogeneity is rarely taken into account in therapies, so it is still essential to look for new specific drugs for leukemia subtypes or even for therapy-resistant cases. Among heterocyclic compounds that attracted a lot of attention because of its wide spread biological activities, the pyrrolo[1,2-a]quinoxaline heterocyclic framework has been identified as interesting scaffolds for antiproliferative activity against various human cancer cell lines. In the present study, novel ethyl 4-[4-(4-substitutedpiperidin-1-yl)]benzyl-phenylpyrrolo[1,2-a]quinoxaline-carboxylate derivatives 1a-l have been designed and synthesized. Their cytotoxicities were evaluated against five different leukemia cell lines, including Jurkat and U266 (lymphoid cell lines), and K562, U937, HL60 (myeloid cell lines), as well as normal human peripheral blood mononuclear cells (PBMNCs). Then, apoptosis study was performed with the more interesting compounds. The new pyrrolo[1,2-a]quinoxaline series showed promising cytotoxic potential against all leukemia cell lines tested, and some compounds showed better results than the reference compound A6730. Some compounds, such as 1a, 1e, 1g and 1h are promising because of their high activity against leukemia and their low activity against normal hematopoietic cells. Structure-activity relationships of these new synthetic compounds 1a-l are here also discussed.
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http://dx.doi.org/10.1016/j.ejmech.2016.02.047DOI Listing
May 2016

Synthesis and biological evaluation of new 1,3-thiazolidine-4-one derivatives of nitro-l-arginine methyl ester.

Chem Cent J 2016 4;10. Epub 2016 Feb 4.

Department of Microbiology, Faculty of Pharmacy, University of Medicine and Pharmacy "Grigore T. Popa", 16 University Street, 700115 Iasi, Romania.

Background: l-Arginine is a semi-essential aminoacid with important role in regulation of physiological processes in humans. It serves as precursor for the synthesis of proteins and is also substrate for different enzymes such as nitric oxide synthase. This amino-acid act as free radical scavenger, inhibits the activity of pro-oxidant enzymes and thus acts as an antioxidant and has also bactericidal effect against a broad spectrum of bacteria.

Results: New thiazolidine-4-one derivatives of nitro-l-arginine methyl ester (NO2-Arg-OMe) have been synthesized and biologically evaluated in terms of antioxidant and antibacterial/antifungal activity. The structures of the synthesized compounds were confirmed by (1)H, (13)C NMR, Mass and IR spectral data. The antioxidant potential was investigated using in vitro methods based on ferric/phosphomolybdenum reducing antioxidant power and DPPH/ABTS radical scavenging assay. The antibacterial effect was investigated against Gram positive (Staphylococcus aureus ATCC 25923, Sarcina lutea ATCC 9341) and Gram negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) bacterial strains. The antifungal activity was also investigated against Candida spp. (Candida albicans ATCC 10231, Candida glabrata ATCC MYA 2950, Candida parapsilosis ATCC 22019).

Conclusions: Synthesized compounds showed a good antioxidant activity in comparison with the NO2-Arg-OMe. The antimicrobial results support the selectivity of tested compounds especially on P. aeruginosa as bacterial strain and C. parapsilosis as fungal strain. The most proper compounds were 6g (R = 3-OCH3) and 6h (R = 2-OCH3) which showed a high free radical (DPPH, ABTS) scavenging ability and 6j (R = 2-NO2) that was the most active on both bacterial and fungal strains and also it showed the highest ABTS radical scavenging ability.Graphical abstract1: ethyl 3-aminopropionate hydrochloride, 2a-j: aromatic aldehydes, 3: thioglycolic acid, 4a-j: thiazolidine-propionic acid derivatives , 5: Nω-nitro-L-arginine methyl ester hydrochloride, 6a-j: thiazolidine-propionyl-nitro-L-arginine methyl ester derivatives.
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http://dx.doi.org/10.1186/s13065-016-0151-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743259PMC
February 2016

Design of α7 nicotinic acetylcholine receptor ligands using the (het)Aryl-1,2,3-triazole core: Synthesis, in vitro evaluation and SAR studies.

Eur J Med Chem 2016 Jan 10;107:153-64. Epub 2015 Nov 10.

Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France. Electronic address:

We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4β2 nicotinic receptor (up to 1 μM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported.
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http://dx.doi.org/10.1016/j.ejmech.2015.11.001DOI Listing
January 2016

Assessment of the Protection of Dopaminergic Neurons by an α7 Nicotinic Receptor Agonist, PHA 543613 Using [(18)F]LBT-999 in a Parkinson's Disease Rat Model.

Front Med (Lausanne) 2015 2;2:61. Epub 2015 Sep 2.

UMR INSERM U930, Université François Rabelais , Tours , France.

The inverse association between nicotine intake and Parkinson's disease (PD) is well established and suggests that this molecule could be neuroprotective through anti-inflammatory action mediated by nicotinic receptors, including the α7-subtype (α7R). The objective of this study was to evaluate the effects of an agonist of α7R, PHA 543613, on striatal dopaminergic neurodegeneration and neuroinflammation in a rat model of PD induced by 6-hydroxydopamine (6-OHDA) lesion. Adult male Wistar rats were lesioned in the right striatum and assigned to either the PHA group (n = 7) or the Sham group (n = 5). PHA 543613 hydrochloride at the concentration of 6 mg/kg (PHA group) or vehicle (Sham group) was intra-peritoneally injected 2 h before 6-OHDA lesioning and then at days 2, 4, and 6 post-lesion. Positron emission tomography (PET) imaging was performed at 7 days post-lesion using [(18)F]LBT-999 to quantify the striatal dopamine transporter (DAT). After PET imaging, neuroinflammation was evaluated in same animals in vitro through the measurement of the microglial activation marker 18 kDa translocator protein (TSPO) by quantitative autoradiography with [(3)H]PK-11195. The DAT density reflecting the integrity of dopaminergic neurons was significantly decreased while the intensity of neuroinflammation measured by TSPO density was significantly increased in the lesioned compared to intact striatum in both groups. However, these both modifications were partially reversed in the PHA group compared to Sham. In addition, a significant positive correlation between the degree of lesion and the intensity of neuroinflammation was evidenced. These findings indicate that PHA 543613 exerts neuroprotective effects on the striatal dopaminergic neurons associated with a reduction in microglial activation in this model of PD. This reinforces the hypothesis that an α7R agonist could provide beneficial effects for the treatment of PD.
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http://dx.doi.org/10.3389/fmed.2015.00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556971PMC
September 2015

Advances in tetrahydropyrido[1,2-a]isoindolone (valmerins) series: Potent glycogen synthase kinase 3 and cyclin dependent kinase 5 inhibitors.

Eur J Med Chem 2015 Aug 27;101:274-87. Epub 2015 Jun 27.

Univ Orleans, CNRS UMR 7311, Institut de Chimie Organique et Analytique, rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France. Electronic address:

An efficient synthetic strategy was developed to modulate the structure of the tetrahydropyridine isoindolone (Valmerin) skeleton. A library of more than 30 novel final structures was generated. Biological activities on CDK5 and GSK3 as well as cellular effects on cancer cell lines were measured for each novel compound. Additionally docking studies were performed to support medicinal chemistry efforts. A strong GSK3/CDK5 dual inhibitor (38, IC50 GSK3/CDK5 32/84 nM) was obtained. A set of highly selective GSK3 inhibitors was synthesized by fine-tuning structural modifications (29 IC50 GSK3/CDK5 32/320 nM). Antiproliferative effects on cells were correlated with the in vitro kinase activities and the best effects were obtained with lung and colon cell lines.
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http://dx.doi.org/10.1016/j.ejmech.2015.06.046DOI Listing
August 2015

The azaindole framework in the design of kinase inhibitors.

Molecules 2014 Nov 28;19(12):19935-79. Epub 2014 Nov 28.

Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans, UMR CNRS 7311, Orléans F-45067, France.

This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.
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http://dx.doi.org/10.3390/molecules191219935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271083PMC
November 2014

Design, synthesis and the biological evaluation of new 1,3-thiazolidine-4-ones based on the 4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one scaffold.

Molecules 2014 Sep 4;19(9):13824-47. Epub 2014 Sep 4.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine and Pharmacy "Grigore T. Popa", 16 University Street, Iasi 700115, Romania.

New thiazolidine-4-one derivatives based on the 4-aminophenazone (4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one) scaffold have been synthesized as potential anti-inflammatory drugs. The pyrazoline derivatives are known especially for their antipyretic, analgesic and anti-inflammatory effects, but recently there were synthesized new compounds with important antioxidant, antiproliferative, anticancer and antidiabetic activities. The beneficial effects of these compounds are explained by nonselective inhibition of cyclooxygenase izoenzymes, but also by their potential scavenging ability for reactive oxygen and nitrogen species. The structure of the new compounds was proved using spectroscopic methods (FR-IR, 1H-NMR, 13C-NMR, MS). The in vitro antioxidant potential of the synthesized compounds was evaluated according to the ferric reducing antioxidant power, phosphomolydenum reducing antioxidant power, DPPH and ABTS radical scavenging assays. The chemical modulation of 4-aminophenazone (6) through linkage to thiazolidine-propanoic acid derivatives 5a-l led to improved antioxidant potential, all derivatives 7a-l being more active than phenazone. The most active compounds are the derivatives 7e, and 7k, which showed the higher antioxidant effect depending on the antioxidant assay considered.
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http://dx.doi.org/10.3390/molecules190913824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270961PMC
September 2014