Guillaume Le Baut

Effects of tumour necrosis factor-α synthesis inhibitors on rat trinitrobenzene sulphonic acid-induced chronic colitis

The fact that tumour necrosis factor-alpha (TNF-alpha) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohns disease, suggests that TNF-alpha synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-alpha synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-betapicolyl-tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphonic acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical score, myeloperoxidase activity, and soluble TNF-alpha release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 34 maleate failed to improve the clinical signs of chronic colitis. After trinitrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-alpha colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P< or =0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamethasone). XC 21 appeared to be as efficient as sulphasalazine in improving colonic inflammation.

New anti-inflammatory N-pyridinyl(alkyl)phthalimides acting as tumour necrosis factor-α production inhibitors

This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-tetrafluorophthalimides known to be inhibitors of tumour necrosis factor-alpha (TNFalpha) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and beta-picolyl), allowing significant inhibition of TNFalpha production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNFalpha production) inhibitory potency could be achieved, notably by 5-fluoro, 4- or 5-nitro, 5-amino and especially tetrafluoro substitution. The most active compound, N-(pyridin-3-ylmethyl)-4,5,6,7-tetrafluorophthalimide (32) (84% inhibition at 10 microM), also produced an anti-oedematous effect in the PMA-induced mouse-ear swelling test. Although less active than dexamethasone, it exerted a marked reduction in ear thickness after oral administration (63% vs. 85% for dexamethasone at 0.2 mMkg(-1)) and remained efficient after topical application (46% vs. 96% for the dexamethasone). It also induced potent inhibition in the rat carrageenan foot oedema test with an ID(50) (0.14 microMkg(-1)) comparable with that of N-(2,6-diisopropylphenyl)phthalimide (4) (0.15 microMkg(-1)).

New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2,3 or 5-(α-azolylbenzyl)-1H-indoles

Six azolyl substituted indoles were synthesized and tested for their activity to inhibit two P450 enzymes: P450 arom and P450 17a. It was observed that the introduction of alpha-imidazolylbenzyl chain at carbon 3 or 5 on indole nucleus led to very active molecules. Compounds 22, 23 and especially 33 demonstrate very high potential against P450 arom. Under our assay conditions of high substrate concentration the IC50 are 0.057, 0.0785 and 0.041 microM, respectively. These compounds are moderate inhibitors against P450 17alpha.

2- and 3-[(aryl)(azolyl)methyl]indoles as potential non-steroidal aromatase inhibitors.

The present study was designed to follow our pharmacomodulation work in the field of non-steroidal aromatase inhibitors. All target compounds 12a–h and 28a–h were tested in  vitro for human placental aromatase inhibition, using testosterone or androstenedione as the substrate for the aromatase enzyme and the IC50 and relative potency to aminoglutethimide data are included. A SAR study indicated that 3-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-1-ethyl-2-methyl-1H-indole (28 g) was a highly potent and selective aromatase inhibitor with IC50 value of 0.025 μM. 28 g was also a weak inhibitor of androstenedione synthesis.

Potential application of plant lipid transfer proteins for drug delivery

Ligand-binding proteins show an increasing interest as drug carriers and delivery systems [Wolf FA, Brett GM. Pharmacol Rev, 1000;52:207-36]. The wide binding properties of plant non-specific lipid transfer proteins such as LTP1 also offer many unexplored possibilities for such a task. In the present paper, by using intrinsic tyrosine LTP1 fluorescence, we survey, for the first time, the binding of wheat LTP1 with various ligands having cosmetic or pharmaceutical applications. LTP1 was found to bind skin lipids such as sphingosine, sphingomyelin, and cerebroside with an affinity of about one micromolar, low enough to allow a slow release of these molecules. Ether phospholipids and an azole derivative BD56 having antitumoral and/or antileishmania properties were also shown to bind LTP1 with similar affinity. Finally, amphotericin B, which is widely used as an antifungal drug, was shown to form a complex with LTP1, although no affinity could be determined. This binding study is a prerequisite for further work aimed at developing applications in LTP-mediated transport and controlled release of low molecular weight drugs.

Synthesis and antifungal activity of new 1-halogenobenzyl-3-imidazolylmethylindole derivatives

A series of 1-benzyl-3-(imidazol-1-ylmethyl)indole derivatives 35-46 were prepared under mild reaction conditions and tested for their antifungal activity. Pharmacomodulation at N(1), C(2) and C(5) of the indole ring and at the level of the alkyl chain (R(1)) was carried out starting from the corresponding 3-acylindoles 6, 7 or 3-formylindoles 11-22. Target imidazolyl compounds 35-46 were obtained in satisfactory yields by CO(2) elimination from the intermediate carbamates. All of the compounds were evaluated in vitro against two human fungal pathogens, Candida albicans (CA980001) and Aspergillus fumigatus (AF980003); amphotericin B, fluconazole and itraconazole were used as references. Seven out of 27 compounds (35b, 35e, 35g, 35h, 36a, 38a and especially 40a) exerted significant antifungal activity against C. albicans, with MIC in the range of 1-6 microg mL(-1). As regards inhibitory activity against A. fumigatus, the MIC figures of most of our compounds were in excess of 20 microg mL(-1) in contrast to the reference drugs, amphotericin B and itraconazole, whose MIC(90) and MIC(80) values were 0.14 and 0.50 microg mL(-1), respectively. The most potent compound, 45a, exhibited MIC value (8 +/- 1 microg mL(-1)) 16-fold higher than that of itraconazole.

Synthesis and antileishmanial activity of new imidazolidin-2-one derivatives

N(3)-acyl, arylsulfonyl and benzyl derivatives of N(1)-(4,6-dimethylpyridin-2-yl), (5-methylthiazol-2-yl) or (3-methylisoxazol-5-yl)imidazolidin-2-ones were synthesized and evaluated as potential antileishmanial agents. Determination of their cytotoxic effect was carried out using MRC5 cells. Two compounds, 1-(4,6-dimethylpyridin-2-yl)-3-(napht-2-ylsulfonyl)imidazolidin-2-one, 18, and 1-(3-methylisoxazol-5-yl)-3-(4-bromobenzyl)imidazo-lidin-2-one, 25, exerted significant antileishmanial activity in promastigotes of Leishmania (L) mexicana and Leishmania infantum, with IC(50) in the range of 8-16 micro mol L(-1). Antiparasitical activity of the less toxic compound, 25, was confirmed against intracellular amastigote of L. mexicana, the clinical relevant stage; its low IC(50) value (2.4 micro mol L(-1)) and its favourable toxicity/activity index (11) constitute encouraging results for ongoing pharmacomodulation in the corresponding subseries.

Preparation and pharmacological profile of 7-(α-azolylbenzyl)-1H-indoles and indolines as new aromatase inhibitors

Aromatase (P450 arom) is a target of pharmacological interest for the treatment of breast cancer. New series of 7-(alpha-azolylbenzyl)-1H-indoles and indolines were synthesized as non-steroidal inhibitors of P450 arom. Selectivity was studied towards P450 17alpha enzyme. The most active compound, 1-ethyl-7-[(imidazol-1-yl)(4-chlorophenyl)methyl]-1H-indole 12c exhibited promising relative potency (rp) of 336 (rp of aminoglutethimide=1) and most of the described azoles were active and selective towards P450 arom.

Pyrophtalones VII. Synthèse et activité anti-inflammatoire de (pyridinyl-4)-2 indanediones-1,3 substituées sur le noyau benzénique et/ou sur l'hétérocycle

Access routes to 2-(1,4-dihydro 4-pyridinylidene) indane-1,3-diones diversely substituted on the benzene ring are studied. The regiospecific attack of these β diketoenamines by alkyl iodides leads to N-substituted compounds. These derivatives may be obtained by any of three possible methods: (1) condensation of 4-methyl pyridine with ethyl phthalates in the absence of catalyst; (2) oxidative condensation of N-alkyl pyridinium bromides with indane-1,3-diones; (3) aminolysis of 2-(4-4H-pyranylidene) indane-1,3-diones. Pharmacomodulation by the introduction of oxygen or sulfur containing functions (ether, thioether, alcohol, ketone, acid, ester, amide) on the nitrogen of the basic molecule is not very fruitful; only the acetic derivative 19 manifests marked anti-inflammatory activity unaccompanied by anti-coagulant action. The presence of chloro, nitro or methoxyl groups on 5 after N-substitution by ethyl or piperidinylethyl groups appears to be more favorable. The most active compound 57 decreases prostaglandin production and leukocyte migration without affecting either cyclo-oxygenase or 5-lipoxygenase. Its interference, direct or indirect, with phospholipasic A2 activity may be envisaged in particular.

New N -pyridinyl(methyl)-indole-2- and 3-(Alkyl)carboxamides and Derivatives Acting as Systemic and Topical Inflammation Inhibitors

A series of novel N -substituted-(indol-2-yl)carboxamides (12 - 18) and (indol-3-alkyl)carboxamides (25 - 31) were synthesized and evaluated as inhibitors of the inflammation process. Pharmacomodulation at the level of the amidic nitrogen by incorporation of the previously described pharmacophoric moieties 6-aminolutidine, β -picolylamine, 4-aminopyridine and piperazine was investigated; only two compounds (12) and (31) exhibited significant (~40%) inhibitory effect in the carrageenan-induced rat paw edema after oral administration of a dose of 0.1 mM kg −1. Replacement of the indole core by indazole failed to increase activity. Incorporation of an alkyl chain spacer led to more efficient compounds (46 - 52) especially in the indolepropanamide sub-series. Determination of the efficiency of the most active compounds on topical inflammation, by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay, confirmed the high potency of propanamides (49) and (51) after oral administration: ID50 =0.041 ± 0.013 and 0.042 ± 0.016 mM kg −1 respectively. The less toxic propanamide (51) exerted a high level of inhibitory activity after topical application of 2 × 100 μg/ear: 78 ± 2%.