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Background: The aim of the present work was to set-up compounds that are able to act simultaneously as antimalarial and antioxidants. Trolox, a known antioxidant was chosen as a core structure to ensure the antioxidant activity and contribute to antiplasmodial effect. Results: Ten compounds were prepared in one step and evaluated on chloroquino-sensitive (3D7) and chloroquino-resistant (FcB1) strains of Plasmodium falciparum. The most active compound (3d) shows antiplasmodial activity in the range of chloroquine against chloroquino-sensitive and chloroquino-resistant P. falciparum strain. The antioxidant activity of (3d) was conducted through four tests and was found to be more potent than trolox itself and L-ascorbic acid. Conclusion: Compound (3d) can be considered as an excellent lead molecule for further in vivo studies. This study paves the way for building large chemical libraries to be investigated in the field of malaria., info:eu-repo/semantics/published

Multidrug-resistance protein 1 (MRP1) belongs to the ATP-binding cassette (ABC) transporter family. MRP1 mediates MDR (multidrug resistance) by causing drug efflux either by conjugation to glutathione (GSH) or by co-transport with free GSH (without covalent bonding between the drug and GSH). We recently reported that the calcium channel blocker verapamil can activate massive GSH efflux in MRP1-overexpressing cells, leading to cell death through apoptosis. However, clinical use of verapamil is hampered by its cardiotoxicity. Then, in the search for compounds that act similarly to verapamil, but without major side effects, we investigated xanthones. Herein we show that xanthones induce apoptosis among resistant cells overexpressing MRP1 similarly to the verapamil effect. Among the xanthones studied, 1,3-dihydroxy-6-methoxyxanthone was identified as the most active derivative, able to specifically kill cells transfected with human MRP1 with even greater potency than verapamil. Under the same conditions, the active xanthones have no toxic effect on control (sensitive) cells. Xanthones could therefore be considered as new potential anticancer agents for the selective treatment of MRP1-positive tumors.

International audience; In continuing research that led us to identify chromanone derivatives (J. Med. Chem. 2003, 46, 2125) as P-glycoprotein inhibitors, we obtained analogues able to modulate multidrug resistance (MDR) mediated by the breast cancer resistance protein (BCRP). The linkage of 5-hydroxybenzopyran-4-one to piperazines or phenalkylamines affords highly potent inhibitors of BCRP. By using sensitive (HCT116) and resistant colon cancer cells expressing BCRP, we evaluated the effect of 14 benzopyranone (chromone) derivatives on the accumulation and the cytotoxic effect of the anticancer drug, mitoxantrone. At 10 microM, three compounds increased both intracellular accumulation and cytotoxicity of mitoxantrone in HCT116/R cells with a comparable rate as fumitremorgin C and Gleevec used as reference inhibitors. The most potent molecules 5b and 5c are still active at 1 microM, whereas FTC shows weak inhibition. These molecules do not induce cell death as shown by the cell cycle distribution study, which makes them potential candidates for in vivo studies.

The retention and separation of a series of D,L dansyl amino acids (used as test solutes) on a teicoplanin stationary phase were investigated over a wide range of mobile phase (citrate buffer-methanol, 90:10, v/v) pH. An approach based on the development of various equilibria was carried out in order to describe the retention behavior of the solute in the chromatographic system. The equilibrium constants corresponding to the transfer of the anionic and zwitterionic forms of the dansyl amino acids from the mobile to the stationary phase were determined. These values allowed one to explain the decrease in the retention factor and the associated increase in the separation factor as the eluent pH was increased. Thermodynamic parameter variations were calculated so that the driving forces of the solute association with the teicoplanin phase were derived. This approach indicated that the chiral discrimination was principally controlled by the interaction between the anionic form of the solute and the stationary phase.

The binding of a series of D,L dansyl amino acids (used as test solutes) to immobilized teicoplanin has been investigated over a wide range of sodium citrate buffer concentrations,c (2.5×10−3 to 10−1 M). An approach based on the use of both the Gibbs adsorption isotherm and a solute displacement model was used to describe solute behavior in this chromatographic system. Variation of thermodynamic quantities was calculated from Van't Hoff plots to enable understanding of the forces driving solute association with the teicoplanin phase. An enthalpyentropy compensation study was also performed for further exploration of the interaction mechanisms. The results suggested that variations of solute retention whenc changed were governed by both (i) the salting-out effect of the salt and (ii) competitive displacement of the dansyl amino acids from their teicoplanin binding site by the citrate anion. The study also shows that hydrophobic interactions and hydrogen-bond formation are important to chiral discrimination in this chromatographic system.

A series of 3-N,N-di-n-propylamino-2-chromanones were synthesized as dopamine analogues. The lactone ring was introduced as a means to reduce their propensity to cross the blood-brain barrier and to avoid central side effects, rendering these compounds potentially useful for the treatment of glaucoma. Pharmacological activities were determined in vitro on rat striatum, by examining their capacity to displace the specific binding of the labeled dopaminergic ligand 3H sulpiride or 3H spiperone and 3H SCH 23390 for D2 and D1 sites, respectively. Compound 6a showed a weak dopaminergic activity on D2-receptors and no affinity for D1-receptors, which can be explained, at least in part, by a weak pKa and the presence of an internal hydrogen bonding. Furthermore, computer molecular modelling studies showed that the aromatic ring of 6a was negatively charged in contrast to the classical D2-agonists aminotetralin derivatives, hampering a possible interaction with a negatively charged area of the D2-receptor. These results, taken together, can account for the moderate dopaminergic activities exhibited by these lactone derivatives.

International audience; This review describes the breast cancer resistance protein ABCG2 through its structure, functional roles and involvement in cell multidrug resistance, especially in cancer cells resistance to chemotherapeutics. The different types of known inhibitors are described, some being non-selective, since they also bind to other targets, and others being quite specific such as flavonoids. The different classes of active flavonoids and other polyphenols are described, some as plant natural compounds, but most of them being prepared and derivatized through medicinal chemistry. Quantitative structure-activity relationships of the ability of flavones, chalcones, xanthones, acridones and various benzopyrane/benzofurane derivatives to inhibit ABCG2-mediated drug efflux have led to pharmacophores and molecular models allowing to optimize the available hit compounds and to design new-generation lead compounds. Interestingly, inhibitory flavonoids are quite specific for ABCG2 versus ABCB1 and ABCC1, and appear either non-competitive or partially competitive towards mitoxantrone efflux. Most compounds do not inhibit ATPase activity, and are assumed not to be transported themselves by the transporter. Some acridones, firstly optimized in vitro as potent inhibitors, are indeed efficient in vivo, against human xenografts in SCID mice, more efficiently than gefitinib taken as a control. Future developments should open the way to more efficient/targeted modulators including (i) the potential interest of bimodulation by combining two different inhibitors, (ii) computer-assisted ligand-based drug design for getting more potent and more specific inhibitors, (iii) structure-based drug design from ABCG2 molecular models allowing in silico screening and docking of new inhibitors.

There is evidence that hyperglycemia results in the generation of reactive oxygen species, leading to oxidative stress in various tissues, including vascular system. An important link between oxidative stress, inflammatory response and insulin activity is now well established. The ability of antioxidants to protect against the deleterious effects of hyperglycemia and also to improve glucose metabolism and intake must be considered as leads of choice in diabetes treatment. In addition to their antioxidative activity, many flavonoids were demonstrated to act on biological targets involved in type 2 diabetes mellitus such as: α-glycosidase, glucose cotransporter or aldose reductase. In this context, flavonoids behaving as antioxidants were studied as potential drugs by acting as biological targets involved in diabetes development. In this review, we propose to shed light on antioxidants flavonoids investigated as antidiabetics. A special focus was made to address the structure-activity relationship related to the effect of these naturally occurring molecules on different targets involved in diabetes development.

International audience; We have identified naturally occurring 2-benzylidenebenzofuran-3-ones (aurones) as new templates for non-nucleoside hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) inhibitors. The aurone target site, identified by site-directed mutagenesis, is located in thumb pocket I of HCV RdRp. The RdRp inhibitory activity of 42 aurones was rationally explored in an enzyme assay. Molecular docking studies were used to determine how aurones bind to HCV RdRp and to predict their range of inhibitory activity. Seven aurone derivatives were found to have potent inhibitory effects on HCV RdRp, with IC(50) below 5 μM and excellent selectivity index (inhibition activity versus cellular cytotoxicity). The most active aurone analogue was (Z)-2-((1-butyl-1H-indol-3-yl)methylene)-4,6-dihydroxybenzofuran-3(2H)-one (compound 51), with an IC(50) of 2.2 μM. Their potent RdRp inhibitory activity and their low toxicity make these molecules attractive candidates as direct-acting anti-HCV agents.

A series of 13 novel hybrid molecules designed to possess both free radical scavenging activity and to stimulate the β3-adrenoceptors in order to improve antidiabetic effect and to restore insulin sensitivity was synthesized and evaluated. Compounds were of quinolyl-, isoquinolyl-, pyridoindolyl- or carbazolyloxypropanolamine structure with a terminal amino group of benzopyranolyl-, di-tert-butylphenolyl- or methoxyindolyl-type. Some of the products possessed both the expected activities.

In addition to its critical role is controlling drug availability and protecting sensitive organs and stem cells through cellular detoxification, breast cancer resistance protein (BCRP/ABCG2) plays an important role in cancer cell resistance to chemotherapy, together with P-glycoprotein/ABCB1. A main approach to abolish multidrug resistance is to find out specific inhibitors of the drug-efflux activity, able to chemosensitize cancer cell proliferation. Many efforts have been primarily focused on ABCB1, discovered thirty years ago, whereas very few studies have concerned ABCG2, identified much more recently. This review describes the main types of inhibitors presently known for ABCG2, and how quantitative structure-activity relationship analysis among series of compounds may lead to build up molecular models and pharmacophores allowing to design lead inhibitors as future candidates for clinical trials. A special attention is drawn on flavonoids which constitute a structurally-diverse class of compounds, well suited to identify potent ABCG2-specific inhibitors.

International audience; A series of compounds derived from naturally occurring flavonoids and synthetic analogs have been evaluated on cell lines overexpressing the wild-type breast cancer resistance protein (BCRP/ABCG2) halftransporter. Human ABCG2-transfected cells were used for screening their inhibitory activity. Five new natural compounds obtained from Morus mesozygia Stapf and one synthetic chromone, comprising a flavonoidic scaffold, were also evaluated. Based on the results obtained with a total of 34 compounds, a 3D linear solvation energy QSAR was investigated by VolSurf descriptors of molecular-interaction fields (MIFs) related to hydrophobic-interaction forces, polarisability and hydrogen-bonding capacity. Accuracy of the constructed 3D-QSAR model was attested by a correlation coefficient r2 of 0.77. Shape parameters and hydrophobicitywere revealed to bemajor physicochemical parameters responsible for the inhibition activity of flavonoid derivatives and synthetic analogs towards ABCG2, whereas hydrogen-bond donor capacity appeared highly unfavorable.

P-glycoprotein (Pgp/ABCB1) both accounts for multidrug resistance (MDR) in chemotherapy and contributes to reduce oral bioavailability and brain distribution of drugs. Flavonoids, reported as potent Pgp inhibitors, are able to bind to the cytosolic ATP-binding site and a vicinal hydrophobic pocket. In order to explore the interaction forces governing the affinity of flavonoids towards Pgp, the 3D quantitative structure–activity relationship (QSAR) approach was used to analyze a set of flavonoid derivatives. The variation of affinity towards Pgp was investigated by VolSurf descriptors of Molecular Interaction Fields (MIFs) related to hydrophobic interaction forces, polarizability, and hydrogen-bonding capacity. The 3D linear solvation energy VolSurf model developed here identifies shape parameters and hydrophobicity as the major physicochemical parameters responsible for the affinity of flavonoid derivatives towards Pgp and hydrogen-bonding capacities as minor modulators of this activity. Furthermore, this predictive model (q2 of 0.71) was also validated by use of an external set of 10 flavones.

A series of 59 chalcones was prepared and evaluated for the antimitotic effect against K562 leukemia cells. The most active chalcones were evaluated for their antiproliferative activity against a panel of 11 human and murine cell cancer lines. We found that three chalcones were of great interest as potential antimitotic drugs. In vivo safety studies conducted on one of the most active chalcones revealed that the compound was safe, allowing further in vivo antitumor evaluation.

1,2-dichloroethane (DCE) and o-nitrophenyl octyl ether (o-NPOE), were tested for their ability to form artificial membranes immobilized on polycarbonate (PC) and polyvinylidene fluoride (PVDF) supporting filters using the PAMPA (parallel artificial membrane permeability assays) technique. These detailed studies provided important information on the application domain of the artificial membranes investigated. According to the nature of the organic solvent and the composition of the filter, different permeation behaviours were noted. A double permeation pathway was observed for DCE-coated with PVDF filters since hydrophilic compounds permeated the membrane through aqueous pores created by the interaction of DCE and PVDF filters, while the more lipophilic compounds were trapped in the DCE present on filters. On the other hand, the permeation through PVDF and PC filters coated with o-NPOE did not follow the same mechanisms. An interesting application emerged from these mechanistic studies, namely the use of PC filters for a first high throughput assay designed to measure o-NPOE/water partition coefficients.

The analysis of binding data of a ligand to a macromolecule in the presence of an additive can be classically formulated in terms of the linked functions of Wyman. In the case of a salt, this approach has been extended by Tanford such that the contributions of both salt and water are taken into account. In this paper, the extended Wyman theory was applied to high-performance affinity chromatography (HPAC) in order to define a general model describing the effects of the mobile-phase salts on the ligand binding. Various HPAC literature data, as well as our data concerning dansyl amino acid retention on a vancomycin stationary phase, were examined in relation to this model. From the results, this theoretical approach was considered to be adequate to describe accurately the salt dependence on solute retention. This work shows the importance of taking into account the effects of both ionic species and water in the investigation of relative contributions of the interactions involved in the ligand binding to immobilized receptor.

A series of 13 novel hybrid molecules designed to possess both free radical scavenging activity and to stimulate the β3-adrenoceptors in order to improve antidiabetic effect and to restore insulin sensitivity was synthesized and evaluated. Compounds were of quinolyl-, isoquinolyl-, pyridoindolyl- or carbazolyloxypropanolamine structure with a terminal amino group of benzopyranolyl-, di-tert-butylphenolyl- or methoxyindolyl-type. Some of the products possessed both the expected activities.

Reaction of 2-aminothiazoline with an aromatic aldehyde and diethylmalonate, in basic medium afforded two kinds of regioisomers: 5-oxo and 7-oxo-tetrahydrothioazolopyrimidines. Assignment of the structures of 5-oxo-7-phenyl-2,3,6,7-tetrahydro-5H -thiazolo[3,2-a] pyrimidine-6-ethylcarboxylate (1) and 7-oxo-5-phenyl-2,3,5,6-tetrahydro-7H -thiazolo[3,2-a] pyrimidine-6-ethylcarboxylate (2) were performed using 1H and 13C NMR spectroscopy, including NOE experiments. For each regioisomer, only R∗S∗ trans-diaxial diastereoisomers were isolated and characterized.

Contient un article en anglais de 7 p. intitulé : "Investigation of the structure activity relationship of flufenamic acid derivatives as human TRESK openers". Thèse proposée pour un prix de thèse.; TRESK (Twik Related Spinal cord K+ channel) is a member of the Twin Pore Domain K+ channel (K2P) family responsible for regulating neuronal excitability in dorsal root ganglion (DRG) and Trigeminal Neurons (TG), peripheral neurons involved in pain transmission. As channel opening causes an outward K+ current responsible for cell hyperpolarisation, TRESK represents a new interesting target for pain treatment. However, as no crystal structure exists for this K2P, the mechanisms involved in the opening effect of some ligands are still poorly understood, making the conception of new potent selective openers challenging. In this work we propose a Structure Activity Relationship (SAR) of the known TRESK opener Flufenamic acid (FFA) and some derivatives, investigating the biological effects of chemical modifications and using a human-TRESK (hTRESK) homology model to support the biological results. A plausible binding mode resulted from this study for the tested openers, providing the first predictive view of a hTRESK opener binding site.; TRESK (Twik Related Spinal cord K+ channel) est un membre de la famille des canaux potassiques à deux domaines P (K2P) responsable de la régulation de l'excitabilité neuronale dans les ganglions de la racine dorsale (DRG) et le nerf trijumeau (TG), deux structures nerveuses périphériques impliquées dans la transmission de la douleur. Son ouverture entraîne une sortie massive d'ions K+ qui résulte en l'hyperpolarisation des cellules nerveuses de ces deux structures, faisant de TRESK une nouvelle cible intéressante dans le traitement de la douleur. Cependant, la structure tridimensionnelle de cette protéine n'étant pas élucidée à ce jour, les mécanismes impliqués dans l'effet ouvreur de certains ligands restent mal compris, rendant difficile la conception rationnelle de nouveaux composés ouvreurs. Ce travail propose d'étudier la relation structure activité de l'acide flufénamique (FFA), un ligand ouvreur de TRESK, et de ses dérivés. Dans ce but, l'impact de diverses modifications structurales sur l'effet biologique de ce ligand fut évalué, et un modèle structural tridimensionnel du canal TRESK humain créé par homologie fut utilisé en support des résultats biologiques obtenus. La combinaison des données biologiques et de modélisation moléculaire a permis de révéler la première vue prédictive plausible d'un site actif impliqué dans l'effet ouvreur de TRESK.

La nalbuphine est un analgésique morphinique agoniste-antagoniste très intéréssant pour son effet-plafond sur la dépression respiratoire, évitant tout risque d'arrêt respiratoire. Son utilisation en anesthésie péri-opératoire, lors d'infarctus du myocarde ou pour les douleurs obstétricales procure une analgésie suffisante. L'administration de la nalbuphine par voie rectale est un mode d'administration récent et tout à fait adapté à l'enfant pour qui l'idée de la piqûre est un obstacle à une anesthésie non traumatisante. Toutefois, la pharmacocinétique de la nalbuphine administrée par cette voie n'a jamais été étudiée. Nous avons donc mis au point et validé une nouvelle méthode de dosage de la nalbuphine dans le plasma par chromatographie liquide haute performance couplée à une détection électrochimique après extraction en phase solide. Cette nouvelle méthode s'est avérée être très fiable, sensible, reproductible et rapide à réaliser. La possibilité d'être automatisée rend cette technique tout à fait adaptée au dosage quotidien d'un grand nombre d'échantillons. L'étude des paramètres pharmacocinétiques de la nalbuphine administrée par voie rectale permettra une utilisation optimale de ce morphinique par les médecins-anesthésistes et permettra de valider la voie rectale comme voie d'administration de ce médicament.