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International audience; The aim of this study was to prepare and characterise inclusion complexes of a low water-soluble drug, mefenamic acid (MA), with b-cyclodextrin (b-CD). First, the phase solubility diagram of MA in b-CD was drawn from 0 to 21 Â 10 À3 M of b-CD concentration. A job's plot experiment was used to determine the stoichiometry of the MA:b-CD complex (2:1). The stability of this complex was confirmed by molecular modelling simulation. Three methods, namely solvent co-evaporation (CE), kneading (KN), and physical mixture (PM), were used to prepare the (2:1) MA:b-CD complexes. All complexes were fully characterised. The drug dissolution tests were established in simulated liquid gastric and the MA water solubility at pH 1.2 from complexes was significantly improved. The mechanism of MA released from the b-CD complexes was illustrated through a mathematical treatment. Finally, two in vitro experiments confirmed the interest to use a (2:1) MA:b-CD complex.

Oxidative stress may be the major cause of induction of Shiga toxin-converting (Stx) prophages from chromosomes of Shiga toxin-producing Escherichia coli (STEC) in human intestine. Thus, we aimed to test a series of novel antioxidant compounds for their activities against prophage induction, thus, preventing pathogenicity of STEC. Forty-six compounds (derivatives of carbazole, indazole, triazole, quinolone, ninhydrine, and indenoindole) were tested. Fifteen of them gave promising results and were further characterized. Eleven compounds had acceptable profiles in cytotoxicity tests with human HEK-293 and HDFa cell lines. Three of them (selected for molecular studies) prevent the prophage induction at the level of expression of specific phage genes. In bacterial cells treated with hydrogen peroxide, expression of genes involved in the oxidative stress response was significantly less efficient in the presence of the tested compounds. Therefore, they apparently reduce the oxidative stress, which prevents induction of Stx prophage in E. coli.

A new series of 1-benzyl-3-(imidazol-1-ylmethyl)indoles were synthesized according to a previous 3D-QSAR predictive model and assayed for their antiparasitic activity upon Leishmania mexicana promastigotes. The biological results obtained for these twelve molecules showed an IC(50) ranging from 2.3 to 32 microM and mainly illustrated the importance of the hydrophobic parameter the para-position of the benzyl group. In order to improve the activities of these compounds and to check the potential influence of the electronic parameter on this particular position, a Craig diagram was used to select original electro-donating and lipophilic substituents. Synthesis and biological evaluation of ten new compounds (IC(50) between 2.5 and 5.4 microM) confirmed that only the hydrophobic field is essential for a high level of activity.

A three-dimensional (3-D) structure of human aromatase (CYP 19) was modeled on the basis of the crystal structure of rabbit CYP2C5, the first solved X-ray structure of an eukaryotic cytochrome P450 and was evaluated by docking S-fadrozole and the steroidal competitive inhibitor (19R)-10-thiiranylestr-4-ene-3,17-dione, into the enzyme active site. According to a previous pharmacophoric hypothesis described in the literature, the cyano group of S-fadrozole partially mimics the steroid backbone C(17) carbonyl group of (19R)-10-thiiranylestr-4-ene-3,17-dione, and was oriented in a favorable position for H-bonding with the newly identified positively charged residues Lys 119 and Arg435. In addition, this model is consistent with the recent combined mutagenesis/modeling studies already published concerning the roles ofAsp309 and His480 in the aromatization of the steroid A ring.

The present study was designed to investigate conazoles as new antileishmanial agents. Several 3-imidazolylalkyl-indoles were prepared under mild reaction conditions and pharmacomodulation at N1 and C5 of the indole ring and at the level of the alkyl chain (R) was carried out starting from the corresponding 3-formylindoles 7-10. All target imidazolyl compounds 38-52 were evaluated in vitro against Leishmania mexicana promastigotes; ketoconazole, amphotericin B and meglumine antimoniate were used as references. Eight out of fifteen compounds (40,43,44,47,48, 50, 51 and 52) exerted similar activity to ketoconazole, with IC50 values in the range of 2.10-3.30 microg/mL. However the most potent compound, 1-(2-bromobenzyl)-3-(1H-imidazol-1-ylmethyl)-1H-indole (38), exhibited IC50 value (0.011+/-0.003 microg/mL) 270-fold lower than that of ketoconazole. Four compounds (38, 43, 50 and 52) were also tested against intracellular amastigotes of L. mexicana; compound 38 exhibited the highest activity with an IC50 value of 0.018+/-0.004 microg/mL.

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or alpha-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 microM) ketoconazole exerted similar inhibitory effect (70% inhibition).

The “Groupement des Pharmacochimistes de l’Arc Atlantique” (GP2A) or Group of Medicinal Chemists of the Atlantic Arc is a study group on research and teaching in Medicinal Chemistry, which was created in 1992. It embraces medicinal chemists, mainly working in Faculties of Pharmacy and located in the different regions of the Atlantic Arc in the United Kingdom, France, Spain and Portugal. More recently, this grouping has welcomed new members who do not belong stricto sensu to this area (such as Lille, Saarbruck, Duesseldorf), in the framework of the GP2A network. This Grouping constitutes a focus for the exchange of ideas among scientists (including undergraduates) interested in basic research in medicinal chemistry but also in special areas of research in drug design, including combinatorial chemistry, quantitative structure-activity relationships and molecular modelling. GP2A gives an opportunity, especially to young scientists, to strengthen and extend their collaboration and exchange programmes. The circle is open to external participation and is mainly constituted on the basis of previously existing bilateral co-operations between various laboratories. At the instigation of the starting core, it was decided to hold a scientific meeting each year in the shape of the GP2A Conferences. In 2007, the Conferences were held in Bordeaux (University of Bordeaux 2 – Region Aquitaine) and were organized by the department of “Pharmacochimie” – EA 4138. At the start of the year 2007, there were more than 18,500 students in the University of Bordeaux 2 and a wide programme of courses is offered in medicinal & pharmaceutical sciences, oenology, sports, cognitic, social & human sciences. The main topics of the 2007 edition September 6 & 7, concerned microwave-assisted medicinal chemistry, conception and synthesis of new derivatives in the fight against cancer and parasitic diseases, place of crystallography in pharmaceutical chemistry, and development of radiopharmaceuticals. The steering committee makes a point of thanking all the young researchers of the various GP2A laboratories for the presentation of their work. Previous GP2A Conferences took place in Bordeaux (1992), Caen (1993), Cardiff (1994), Angers (1995), Glasgow (1996), Rennes (1997), Caen (1998), Cardiff (1999), Tours (2000), Nantes (2001), Caen (2002), La Rochelle (2003), Rennes (2004), Angers (2005), Bath (2006) and Bordeaux (2007); we look forward to attending an exciting meeting in Caen in 2008 (May 28–30).

(2004). 12th European Conference of GP2A—La Rochelle 2003. Journal of Enzyme Inhibition and Medicinal Chemistry: Vol. 19, No. 6, pp. 449-449.