J.-M. Robert

Synthesis of N-Pyridinyl(methyl)-1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides and analogues and their anti-inflammatory activity in mice and rats

The topical anti‐inflammatory activity of a series of N‐pyridinyl(methyl)1,2‐dihydro‐4‐hydroxy‐2‐oxoquinoline‐3‐carboxamides, analogues of roquinimex, has been evaluated by measuring their inhibitory effect in the phorbol myristate acetate (PMA)‐induced mouse ear swelling test, used as a screening test.

Inhibition of parasite protein kinase C by new antileishmanial imidazolidin-2-one compounds.

The protein kinase C (PKC) family of isoenzymes mediate a wide range of signal transduction pathways in many different cells lines. Little is known regarding the presence and functional roles of PKC in Leishmania spp. Here we report the inhibition of parasite PKC by new imidazolidinone compounds. The most active derivative 7 showed an important activity (IC 50 =9.9 μM) against the clinical relevant stage of parasites in comparison with Glucantime ® (IC 50 =464.5 μM), without inducing toxicity on human fibroblast cells (IC 50 =102 μM). Pretreatment of intact parasites with 10 μM of compound 7 inhibited 80% of PKC activity. At the same concentration, this compound inhibited 70% of the parasite-host cell invasion process. An in vivo model showed that compound 7 reduced the liver parasite burden by 25% and spleen parasite burden by 44%. These results provide the first evidence that PKC plays a critical role in the invasion process. Thus Leishmania PKC activity could be a relevant therapeutic target and the imidazolidinones novel antileishmanial candidates.

Cholinesterase Inhibition by Derivatives of 2-Amino-4,6-Dimethylpyridine

Derivatives of 2-amino-4,6-dimethylpyridine, aryl(alkyl)carboxamides, thiocarbamides and amidrazones, already known for their anti-inflammatory properties, were found to be moderately active inhibitors of acetyl and butyrylcholinesterase. Quantitative structure-activity relationships showed that the binding affinity was enhanced by the following structural modifications: (1) increase in molecular volume, (2) decrease in the energy of the lowest unoccupied molecular orbital, (3) insertion of a methylene group between the amide carbonyl and the aromatic ring, (4) replacement of the amide oxygen by sulfur. The affinity remained, however, weaker than that of the specific inhibitor 9-amino-1,2,3,4-tetrahydroacridine (tacrine). The association of anti-inflammatory and cholinesterase inhibiting activities within the same compound may prove useful for the treatment of Alzheimers disease.

N-Pyridinyl(alkyl)polyhalogenobenzamides Acting as TNF-α Production Inhibitors

A series of N-pyridinyl(methyl)fluorobenzamides issued from 2,4-dimethyl-6-aminopyridine and 3-aminomethylpyridine were synthesized and evaluated as inhibitors of TNF-α production. Although less active than the corresponding phthalimides, several pentafluorobenzamides exhibited significant activity at 10 μM. N-(4,6-dimethylpyridin-2-yl)pentafluorobenzamide was selected for a preliminary in-vivo assay. Although its inhibitory activity against carrageenan-induced rat paw oedema was moderate, it induced a significant reduction in ear thickness in the PMA-induced mouse ear-swelling test (49± 6% inhibition after a dose of 0.1 mM kg−1, p.o.).

3-Sulfure de 3-mercapto-5,7-diméthyl-2-phényl-3H-[1,4,2]diazaphospholo[1,5-a]pyridinium

The entire molecule of 5,7-dimethyl-2-phenyl-3-thioxo-3H-[1,4,2]diazaphospholo[1,5-a]pyridinium-3thiolate, C 14 H 13 N 2 PS 2 , with the exception of the two S atoms, is approximately planar. The π electrons of the N(7)-C(8) bond are partially conjugated with those of the phenyl and pyridinyl rings. The P-C and P-S bond lengths are not significantly different to distances in related compounds. However, the P-S bonds are shorter than terminal P-S bonds in thiophosphates. The P-N distance [1.819 (3) A] indicates partial ionic character

4-(4,6-Diméthylpyrid-2-yl)-5-éthyl-3-(furan-2-yl)-4H-1,2,4-triazole

The title compound has anti-inflammator y properties. The three rings in the molecule are planar with dihedral angles between their least-squares planes of 70.20 (8), 68.48 (9) and 9.5 (4) °. The structure can be regarded as being composed of two layers of molecules which spread out along the (101) plane. Its cohesion is due to van der Waals interactions.

Synthesis and hypolipidemic activity of N-pyridinyl borodipeptidylamides

Abstract A series of borodipeptide derivatives 7–9 , which contain a 6-amino-2,4-dimethylpyridine moiety, was prepared in 3 steps. They were evaluated as hypolipidemic agents in rodents at 20 mg/kg per day. The methioninamide and phenylalaninamide derivatives were the most potent compounds demonstrating hypocholesterolemic and hypotriglyceridemic activities in rats. After 14 days, the activity of these compounds was superior to that of clofibrate, at a dose of 200 mg/kg per day.

N2-(4,6-diméthylpyrid-2-yl)-N1-méthylpyrazine-2-carboxamidine

The title molecule, C 13 H 15 N 5 , shows a cis configuration. It comprises three approximately planar moieties: an N 2 -(4,6-dimethylpyridine), an N 1 methyl-carboxamidine group and a pyrazinyl ring. To avoid steric hindrance, the two rings are twisted out of the plane of the imine double bond. There is a delocalized orbital over the amidine group. The structure comprises two chains of molecules which spread out along the two 2 1 axes situated in the (101) plane. In each chain, the molecules are linked to one another by an N−H...N hydrogen bond [2.976 (2) A, 160 (2)°]

4-(4,6-Diméthylpyrid-2-yl)-5-éthyl-3-phényl-4H-1,2,4-triazole

The title compound, C 17 H 18 N 4 , is a structural analogue of N-(4,6-dimethylpyrid-2-yl)benzamide, with a triazolic heterocycle instead of the amide function, affording stronger anti-inflammatory properties. The three rings in the molecule are planar with dihedral angles between their least-squares planes of 73.4 (2), 70.7 (2) and 38.8 (4) o . The crystal structure can be regarded as a stack of molecular layers parallel to the (001) plane

N-(4,6-Diméthylpyrid-2-yl)-2-(3-nitrophényl)acétamide

The molecule of the title compound can be regarded as being composed of two parts, an N-(4,6-dimethylpyrid-2-yl)acetamide group and a 3-methylnitrobenzene group, which share the C(9) atom. The two parts are approximately planar. The least-squares planes through the pyridyl and phenyl rings make an angle of 64.5 (1) o . An intramolecular hydrogen bond [C(3)-H(3)...O(18):2.870 (4) A, 114 (3) o ] forms a pseudo ring and contributes to the planarity of the N-(4,6-dimethylpyrid-2-yl)acetamide group. The molecules are linked together by the N(7)H(7)...O(18 i ) hydrogen bond [(i) x, 1/2-y, 1/2+z; 2.859 (3) A, 170 (3) o ]. They form two chains parallel to the c axis and related by a centre of symmetry