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A series of arylhydrazones derived from various 6,8-diacetoxy- or 6,8-dihydroxy-9-oxo-9H-xanthene carboxaldehydes were synthesized and evaluated for their in vitro antifungal properties against two human pathogenic yeasts (Candida albicans and C. krusei) according to a diffusion method. The activity was strongly dependent from the position of the (1-arylhydrazinyl-2-ylidene)methyl chain in the xanthone molecular skeleton. Compounds having the nitrogen side chain in the 4-position, with a further halogen substitution on the terminal phenyl ring showed fungistatic effects. Within this series, the 4-fluorophenylhydrazinyl derivative 13g exhibited the highest activity, particularly against C. krusei, with a greater efficacy than that of econazole, used as reference.

Racemic 4-[13C]catechin 14 has been synthesized in ten steps starting from potassium [13C]cyanide. The intermediate chalcone 9 was formed by acylation of the benzylated phloroglucinol 7 with the caffeic acid synthon 6, using the trifluoroacetic mixed anhydride. The flavonoid skeleton was then obtained by previously described reactions such as the reduction of chalcone 9 and dihydroxylation of flavene 11. Such [13C]-labelled polyphenols should prove to be useful tools for human biological investigations.

Polymethoxylated and polyhydroxylated derivatives of 2-amino-4-arylthiazoles bearing a halogenobenzenesulfonamide moiety at position 2 were synthesized as azole antifungal analogues. X-ray crystallography studies revealed the predominance of the 2-imino-2,3-dihydrothiazole form in the amino/imino tautomerism. In vitro assays against various pathogenic fungal strains (Candida and Trichophyton species) showed no activity in comparison to econazole as reference. These results are discussed on the basis of the estimated global lipophilicity of the molecules (Rekker's method) and the π-electron distribution (Mulliken population analysis, AM1 method) within the five-membered heterocycle.

Torasemide, a loop diuretic, has been reported to relax dog coronary artery precontracted by thromboxane A2 (TXA2), an endogenous prostanoid involved in cardiovascular and pulmonary diseases. N-cyano-N′-{[4-(3′-methylphenylamino)pyrid-3-yl]sulphonyl}homopiperidinoamidine (BM-144) and N-isopropyl-N′-[5-nitro-2-(3′-methylphenylamino)-benzenesulphonyl]urea (BM-500), chemically related to torasemide, have been examined for their TXA2 antagonism. The affinity (IC50, the concentration resulting in 50% inhibition) of BM-144 and BM-500 for the TXA2 receptor of washed platelets from man was 0.28 and 0.079 μM, respectively. This is better than for sulotroban (IC50 = 0.93 μM) but less than for SQ-29548 (IC50 = 0.021 μM), two TXA2 antagonists used as reference. The aggregation of platelets from man induced by arachidonic acid was prevented by BM-144 (IC50 = 9.0 μM) and by BM-500 (IC50 = 14.2 μM). Similar results were obtained by use of U-46619, a TXA agonist, as aggregating agent (BM-144, IC50 = 12.9 and BM-500, IC50 = 9.9 μM). The contracting effect of U-46619 on rat stomach strip was abolished by BM-144 (IC50 = 1.01 μM) and BM-500 (IC50 = 2–54 μM). Both drugs (BM-144: IC50 = 0.12 and BM-500: IC50 = 0.19 μM) also relaxed rat aorta precontracted by U-46619; both were more potent than sulotroban (IC50 = 1.62 μM). The two torasemide derivatives (100 μM) did not significantly affect the myo-stimulating effect of some prostaglandins (PGE2, PGI2, PGF2α) or aorta contraction elicited by KCl (30 mM). They did not modify rat diuresis after administration of a 30-mg kg−1 dose. In conclusion, BM-144 and BM-500 can be regarded as novel non-carboxylic TXA2 receptor antagonists and offer a novel template for the design of more potent molecules.

2,4-Dichloro-N-[2,3-dihydro-4-(2,5-dimethoxyphenyl)thiazol-2-ylidene]benzenesulfonamide, C 17 H 14 Cl 2 N 2 O 4 S 2 , crystallizes in space group P1 with two independent molecules. The structural parameters do not indicate a tautomeric equilibrium but a single imino form. The main differences between the two crystalline forms lie in the intramolecular hydrogen bonding and the relative orientation of the methoxy groups. Attractive intermolecular interactions occur and are responsible for the crystalline cohesion.

A series of new 2-[(arylsulfonyl)imino]-2,3-dihydrothiazolyl derivatives substituted on the heterocyclic N by a phenoxyacetic moiety was prepared according to a Hantzsch's synthesis between N, N'-disubstituted thioureas and chloroacetaldehyde. The regiochemistry of the cyclocondensation reaction was established by high resolution NMR methods. Potential thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonism was evaluated using human platelet aggregation assays and radioligand binding studies. The results showed that the affinity for the TxA2/PGH2 receptor was strongly dependent on the position of the oxyacetic acid side chain. On the basis of the X-ray crystal analysis of compound 9f, a molecular modelling was undertaken on compounds 3d, 3e, and 3f. Comparison with the 3D structure of sulotroban was discussed.

Summary The synthesis of a thienyl dihydropyridine series according to the Hantzsch method is described. The influence of these derivatives on intracellular calcium ([Ca + ]) in GH3 cells was evaluated in vitro using spectrofluorimetry with indol as Ca + f fluorescent probe. We compared their effects on [Ca + ]i and hormone release with those of nifedipine. The most active tested compounds on [Ca + ]i were those methylated on the 3-position of the thienyl ring (activity was about 75% of nifedipine). Interestingly, the most efficient compounds on [Ca + ]i were also the most efficient on hormone release.

Summary A series of 1,2-benzisoxazole-3-carboxamides derived from tertiary cycloalkylamines was synthesized and evaluated for affinity for serotonergic (5-HT 3 and 5-HT 4 ) and dopaminergic (D 2 ) receptors using radioligand binding assays. The majority of compounds displayed a very weak affinity for the studied neurotransmitter receptors. Only amides containing a conformationally rigid system retained a relative 5-HT 3 receptor affinity. The presence of a quinuclidine group affected receptor interaction more favorably than the tropane framework.

A series of 3-(2-thienyl)- and 3-(1-imidazolyl)-1,2-benzisoxazoles as well as some isomeric benzoxazoles were synthesized and tested in vitro for their inhibitory effect on arachidonic acid-induced human platelet aggregation. The most active compound (7-methoxy-3-(2-thienyl)-1,2-benzisoxazole 5c) was nearly 20–30-fold more potent than acetylsalicylic acid in inhibiting platelet aggregation. Structure-activity relationships within the series are briefly discussed.

N-tosyl-oxiraneethylamines undergo cyclization upon treatment with aqueous sodium hydroxide to afford either N-tosyl-azetidinemethanols or N-tosyl-pyrrolidin-3-ols in high yields. The change in regioselectivity of this cyclization process is quite dependent on the location of a pentamethylene substitution in the chain connecting the nitrogen with the oxirane ring.

Gram amounts of 13C-labelled dimer (−)-procyanidin B3 5 were prepared from 1-[13C]acetic acid by coupling the optically labelled flavan-3,4-diol (+)-7 with protected natural catechin (+)-3 in acidic medium.

The regioselectively 13C-labelled (−)-procyanidin B3 was prepared in eight steps from 1-[13C]-acetic acid.

A series of new 2-[(arylsulfonyl)imino]-2,3-dihydrothiazolyl derivatives substituted on the heterocyclic N by a phenoxyacetic moiety was prepared according to a Hantzsch's synthesis between N, N'-disubstituted thioureas and chloroacetaldehyde. The regiochemistry of the cyclocondensation reaction was established by high resolution NMR methods. Potential thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonism was evaluated using human platelet aggregation assays and radioligand binding studies. The results showed that the affinity for the TxA2/PGH2 receptor was strongly dependent on the position of the oxyacetic acid side chain. On the basis of the X-ray crystal analysis of compound 9f, a molecular modelling was undertaken on compounds 3d, 3e, and 3f. Comparison with the 3D structure of sulotroban was discussed.

Polymethoxylated and polyhydroxylated derivatives of 2-amino-4-arylthiazoles bearing a halogenobenzenesulfonamide moiety at position 2 were synthesized as azole antifungal analogues. X-ray crystallography studies revealed the predominance of the 2-imino-2,3-dihydrothiazole form in the amino/imino tautomerism. In vitro assays against various pathogenic fungal strains (Candida and Trichophyton species) showed no activity in comparison to econazole as reference. These results are discussed on the basis of the estimated global lipophilicity of the molecules (Rekker's method) and the π-electron distribution (Mulliken population analysis, AM1 method) within the five-membered heterocycle.

A series of arylhydrazones derived from various 6,8-diacetoxy- or 6,8-dihydroxy-9-oxo-9H-xanthene carboxaldehydes were synthesized and evaluated for their in vitro antifungal properties against two human pathogenic yeasts (Candida albicans and C. krusei) according to a diffusion method. The activity was strongly dependent from the position of the (1-arylhydrazinyl-2-ylidene)methyl chain in the xanthone molecular skeleton. Compounds having the nitrogen side chain in the 4-position, with a further halogen substitution on the terminal phenyl ring showed fungistatic effects. Within this series, the 4-fluorophenylhydrazinyl derivative 13g exhibited the highest activity, particularly against C. krusei, with a greater efficacy than that of econazole, used as reference.

The reaction of N-tosly-oxiranemethylamines with aqueous sodium hydroxide affords N-tosyl-aziridinemethanols in excellent yields, through the intramolecular epoxide ring opening by the nitrogen atom of the tosylamino group.

Resolution of racemic synthetic tetra- O -benzylcatechin 2 is described, through the formation of esters 5 and 6 derived from dibenzoyl- l -tartaric acid. The diastereoisomer of the natural series 6 was separated by crystallization, the other one being an oil. This process allowed us to prepare enantiomerically pure (+)-catechin 8 in high yield. The pure isomer in the ent -series 9 could be obtained, following the same scheme of reactions.

Some (3,5-di-ert-butyl-4-hydroxybenzylidene) cyclanones were synthesized and evaluated for anti-inflammatory activity in carragenin-induced rat paw edema assay. These compounds are slightly less active than phenylbutazone. Their inhibitory effects in vitro on human platelet aggregation have been also examined. The present study shows that the inhibitor profile of the tested compounds on platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP) bears similarly to that of acetylsalicylic acid. The free radical scavenging activity against 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical was measured by Electron Spin Resonance spectrometry. All the studied compounds scavenge the DPPH radical, dose dependently.

The cyclisation of N -tosyl-oxiranepropylamines is accomplished in aqueous basic medium and in anhydrous acid medium as well. In most cases, this reaction occurs by a regiospecific 5- exo-tet . ring closure and affords N -tosyl-2-pyrrolidinemethanols in high yields. The formation of N -tosyl-3-piperidinols through endo attack on the epoxide linkage is observed only in systems exhibiting geometric constraints in the transition state. These cyclisations are accompanied by inversion of configuration at the carbon undergoing nucleophilic attack. Thus, the N -tosyl-oxiranepropylamines cyclisation opens up an efficient entry to functional pyrrolidines and is expected to find useful applications in synthesis.

A series of anti-thrombotic aryl thienyl-ketones and -thioketones was assayed in vitro for their inhibitory effect on malondialdehyde (MDA) production induced by arachidonic acid in human platelets. For several compounds MDA formation was strongly inhibited indicating that the anti-platelet target was situated on the cyclooxygenase pathway. A comparison between the inhibition constant Ki and the IC50 values revealed competitive inhibition kinetics. The molecular structure of one active compound was analysed by X-ray diffraction and theoretical calculations to provide information on its electronic and lipophilic properties.

Resume De nouveaux 3-aryl-4,5-dihydro-5-(5-nitro-2-furyl)-1 H -pyrazoles ont ete synthetises par condensation de l'hydrazine ou de la methylhydrazine sur diverses arylpropenones nitrofuraniques. Leur activite antibacterienne a ete evaluee in vitro . Les composes prepares sont inactifs a l'egard des germes a Gram negatif etudies. Par contre, sur les 11 derives essayes, 9 manifestent une legere activite vis-a-vis de Streptococcus faecalis , et a un degre moindre vis-a-vis de Staphylococcus aureus , les derives les plus interessants etant les N -acetyl et N -formyl, 4,5-dihydro-3-(3,4-dimethoxy-phenyl)-5-(5-nitro-2-furyl)-1 H -pyrazoles.

14C-L-phenylalanine is incorporated into a range of polyphenolic compounds when fed to grape cell cultures. Optimisation of several parameters such as the quantity of precursor applied and the duration of metabolism led to incorporation yields of 15% and to specific activities of 875 mu Ci g(-1) in stilbenes. Purification of the products by several chromatographic steps is reported. Both trans- and cis-resveratrols were easily obtained by enzymatic hydrolysis of their corresponding glucosides, with specific activity of 1200-1400 mu Ci g(-1). The specific radioactivity obtained for all the compounds is suitable for in vivo feeding trials to trace their metabolic fate when consumed by animals and for in vitro activity mechanism studies. Indeed, these polyphenols seem to be implicated in the health benefits associated with regular and moderate wine consumption but little is known about their pharmacokinetics and cellular uptake.

The DNA triplex stabilization property of seven natural anthocyanins (five monoglucosides and two diglucosides) has been measured by the mean of triplex thermal denaturation experiments. We have noticed a difference between the diglucosides that do not modify this melting temperature and the monoglucosides (namely 3-O-beta-D-glucopyranoside of malvidin, peonidin, delphinidin, petunidin and cyanidin) which present a weak but significant stabilizing effect. It appears clearly that the difference between the two series could be due to the supplementary sugar moiety at the 5 position for the diglucosylated compounds, that would make them too crowded to allow interaction with the triplex. Among the monoglucoside series, the most active compounds are the only ones to embody a catechol B-ring in their structure that could be important for such an interaction. The need to have pure and fully characterized compounds to run these measurements, made it possible for us to unambiguously assign the 1H and 13C NMR spectra with the help of 2D NMR experiments. Thus, missing data of compounds not totally described earlier, are provided herein.

Pharmacomodulation of torasemide, a diuretic sulfonylurea, led to the discovery of two novel diuretics, a sulfonylthiourea (BM 20) and a sulfonylcyanoguanidine (BM 106). BM 27, a lipophilic sulfonylurea, exhibited neuroprotective properties associated to an anticonvulsant activity. As BM 27, two lipophilic sulfonythioureas (BM 11 and BM 34) revealed an anticonvulsant profile similar to that of phenytoin. Finally the synthesis of torasemide derivatives led to the development of a sulfonylcyanoguanidine (BM 144) with a thromboxane A2 antagonist potency.

Some new oximinoalkanoic (n = 2,3,4) esters and acids derived from methoxyphenylthienyl ketones have been synthesized and evaluated in vitro for their inhibitory effects on arachidonic acid-induced human platelet aggregation. Of the eighteen oximinoethers tested the most active derivatives, which were four times more active as aspirin, belonged to the para methoxy series with Z configuration and n = 2 or 3. Thrombocyten-aggregationshemmende Methoxyphenylthienyl-Ketoxim-Ether: Synthese und Strukutur-Wirkungs-Beziehungen Eine Reihe von neuen Oximinocarbonnsaureestern (n = 2,3,4) und -sauren, strukturverwandt mit Methoxyphenylthienyl-Ketonen wurde synthetisiert und deren Hemmwirkung in vitro auf die Arachidonsaure-induzierte menschliche Blutplattchenaggregation bewertet. Im Vergleich zu der Hemmwirkung von Aspirin, wird gezeigt, das unter den achtzehn gepruften Oximinoethern, die wirksamsten Verbindungen 4 mal so wirksam wie Aspirin waren. Sie weisen eine Methoxygruppe in para-Stellung mit Z-Konfiguration und n = 2 oder 3 auf.