A simple and effective method for the thionation of amides to thioamides using Al2O3-supported P4S10

A simple and effective method for the thionation of amides to thioamides using Al2O3-supported F4S10 was developed and applied to a series of amides including some heterocyclic examples, The reaction was best performed in anhydrous dioxane at reflux temperature. Yields ranging from 62 - 93% are comparable to, or superior to those obtained with Lawesson's reagent. The method uses inexpensive reagents and has the advantage that reagent-derived byproducts may be removed by a simple hydrolytic workup rather than by chromatography, as required for Lawesson's reagent

Synthesis of 2(3H)-benzoxazolone derivatives as potential melatonin receptor ligands

This article reports the synthesis of new 2(3H)-benzoxazolone-based ligands for the melatonin receptors in which an acetamidopropyl side-chain was incorporated. Construction of the acetamidopropyl moiety was achieved via a Wadsworth-Emmons approach. Although these compounds can be seen as derivatives of N-[3-(3-methoxyphenyl)propyl]acetamide (MPPA), which is the exact analogue of melatonin in which the 1,2-indole nitrogen atoms are deleted, they exhibit lower affinities for the melatonin receptors probably due to an unfavourable steric bulk and hydrophilic interactions

Synthesis of 6-cycloalkyl-2(3H)-benzoxazolones and benzoxathiazolones via 6-tri-N-butyltin intermediates

Friedel-Crafts acylation of highly activated aromatic nuclei is rendered difficult by the fact that extensive complexation of the substrate by the Lewis acid catalyst inevitably takes place, which deactivates more or less completely such reagents. 2(3H)-benzoxazolones and their sulfur bioisosters were chosen as model molecules in an effort to search for an efficient alternative method to the Friedel-Crafts reaction. 6-Cyclo-alkylcarbonyl-3-methyl-2(3H)-benzoxazolones and benzothiazolones which cannot be synthesized by classical Friedel-Crafts approach are expeditiously obtained via tributyltin intermediates to afford the desired compounds in good yields

Les dérivés chlorés du Bisphenol A inhibent l’activité du récepteur humain à la FSH

International audiencePlusieurs données épidémiologiques associent l’exposition au bisphénol A (BPA) avec des anomalies de la fonction de reproduction. Notre équipe a récemment montré que le BPA inhibe l’action de la FSH sur son récepteur (FSHR). La décontamination de l’eau est réalisée par chloration ce qui entraîne la formation de dérivés chlorés du BPA (mono, di, tri et tétra chlorés) (BPA-Clx), qui se retrouvent dans les milieux naturels et dans les matrices biologiques. L’objectif de ce travail est de déterminer les effets des BPA-Clx sur l’activité du FSHR. Nous avons utilisé une lignée de cellules CHO exprimant de façon stable le FSHR humain, dont l’activité est évaluée en mesurant la production d’AMP cyclique (AMPc). Les dérivés chlorés sont obtenus dans un mélange CH2Cl2/THF en présence de chlorure de sulfuryle et purifiés par LC/MS/MS. Tout d’abord nous avons vérifié la non-cytotoxicité des composés (test MTT). Environs 10−7 M de BPA réduit la production d’AMPc stimulée par la FSH de façon dose-dépendante d’environ 40 %. De la même façon, les BPA-Clx diminuent de 30 % la réponse à la FSH, sans modifier l’activité basale du récepteur, suggérant un effet allostérique négatif. Le BPA-Cl4 (10−8 M) est le modulateur négatif le plus puissant de la réponse FSH, suivi par le BPA-Cl3 (10−7 M) et les BPA-Cl2 et BPA-Cl1 (10−5 M). Ces résultats montrent pour la première fois que, comme le BPA, les BPA-Clx peuvent également être considérés comme perturbateurs endocriniens et avoir des effets reprotoxiques qu’il reste à mieux caractériser

An expeditious one-pot synthesis of N-substituted 6-nitroindoles from indolines

This paper reports an one-pot method for the concomitant alkylation - oxidation (aromatization) of indolines, particularly effective to get easy access to N-alkyl-6-nitroindoles, which are useful platforms in medicinal chemistry. N-alkyl-6-nitroindoles are obtained in good yield (64-91%) by reaction at room temperature in non-degassed DMF of 6-nitroindoline, an alkyl halide, and NaH as base. The presence of NaH appears to be essential for a high yield conversion

Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part II: Influence of the substitution on the benzyl moiety on the affinity for D-2L, D-4.2, and 5-HT2A receptors

In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D-2L, D-4.2, and 5-HT2A receptor affinity was evaluated. In the 1-naphthamide series most compounds were highly selective for D-4.2 over D-2L, and 5-HT2A receptors. Halogen and methyl substitution in position 3 or 4 of the benzyl group increased D-4.2 affinity. In the 2-naphthamide series a similar high D-4.2 over D-2L selectivity was retained while 5-HT2A affinity was increased. 3-Methoxy, 3-methyl, and 4-methyl substituents were favorable for D-4.2 affinity while halogens reduced affinity. 2-Naphthamides with a 3-bromo- or a 3-methyl group were mixed D-4.2/5-HT2A ligands similar to their unsubstituted parent compound. All compounds from both series with significant affinity for D-4.2 and 5-HT2A receptors were antagonists. (c) 2007 Elsevier Ltd. All rights reserved

Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part I: Influence of the substitution on the basic nitrogen and the position of the amide on the affinity for D-2L, D-4.2, and 5-HT2A receptors

A series of 1- and 2-naphthamides has been prepared and tested for in vitro binding to D-2L, D-4.2, and 5-HT2A receptors. Different compounds display selectivity for D-4.2 and 5-HT2A receptors versus D-2L receptors. N-(1-Arylalkyl-piperidin-4-yl) carboxamides have higher affinities than the corresponding N-(4-arylalkylamino-piperidin-1-yl) carboxamide analogues. A benzyl moiety in position 1 of the piperidine in the 2-naphthamide series (2) appears to be the best choice for a favorable interaction with D-4.2 and 5-HT2A receptors. Increasing the linker length between the phenyl ring and the basic nitrogen led to a decreased affinity for these receptors. In the 1-naphthamide series, the most potent D-4.2 ligand (7) possesses a phenylpropyl moiety while its affinity for 5-HT2A receptors is strongly reduced. All compounds with significant affinity for D-4.2 and 5-HT2A receptors were antagonists. (c) 2007 Elsevier Ltd. All rights reserved

New pyridobenzodiazepine derivatives: Modifications of the basic side chain differentially modulate binding to dopamine (D-4.2, D-2L) and serotonin (5-HT2A) receptors

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D-4.2, D-2L, and 5-HT2A receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K-i > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D-4.2 and 5-HT2A receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-metbylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo [3.2.1] octane derivatives (23, 38) involved a slight reduction of the affinity at D-4.2 and 5-HT2A receptors while the affinity at D-2L receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D-4.2 receptors but some of these molecules (24, 25, 41) presented a significant 5-HT2A binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D-4.2 and 5-HT2A affinity (K-i = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties

Synthèse et évaluation biologique de dérivés halogénés du Bisphénol A

International audienceLes perturbateurs endocriniens (PE) ont été définis par l’Agence de Protection et de l’environnement des États Unis comme substance exogène qui altèrent les fonctions du système endocrinien et induisent des effets néfastes sur la santé d’un organisme intact. Le Bisphénol A (BPA) est un PE qui interfère avec la synthèse, métabolisme, transport, affinité des hormones naturelles. L’utilisation du BPA est tellement répandue dans l’environnement qu’il provoque de nombreux effets secondaires (cancers, anomalies du développement, reprotoxicité, …). Le BPA est ubiquitaire, il est retrouvé dans les sols, l’air et l’eau. Lors du traitement de l’eau du robinet, la dernière étape consiste à traiter avec du chlore afin d’éliminer des bactéries, cependant cette chloration mène également à la formation de dérivés chlorés du BPA (ClxBPA). De plus la présence d’ions bromures dans l’eau, conduit à la formation de dérivés bromés du BPA (BrxBPA). Nous présenterons la synthèse de ces composés ClxBPA, BrxBPA qui servent de témoins analytiques dans l’analyse d’échantillons biologiques humains ou afin d’évaluer leur toxicité. Une cohorte de femmes enceintes a permis de recueillir leur eau de boisson, des fluides biologiques (urine, colostrum) dont les analyses LC/MS-MS et GC/MS-MS seront détaillées sur leurs teneurs en dérivés halogénés du BPA. Enfin, les dérivés ClxBPA, BrxBPA ont été évalués in vitro sur le récepteur Follitropine (FSHR). Ces composés ne sont pas cytotoxiques (test MTT), ils démontrent un effet allostérique négatif en présence de l’hormone FSH. Ces dérivés sont considérés comme des perturbateurs endocriniens et susceptibles d’avoir des effets reprotoxiques