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Summary Pharmacomodulation of the non-carboxylic NSAID N -(4,6-dimethylpyridin-2-yl)benzamide 1 led to the synthesis of structurally related furan, thiophene and pyrrole carboxamides 3–14 . The derivatives benzenethiocarboxamides 15–18 and heteroaryl-thiocarboxamides 19–22 were also prepared by oxygen/sulfur exchange; this reaction was more efficiently carried out by P 4 S 10 than by Lawesson's reagent. The 20 synthesized compounds were evaluated against peripheral edema by a foot-pad carrageenin-induced edema test. Amides 3–5, 8, 9, 11, 12 and 14 were most active, exhibiting > 90% inhibition after oral administration of 0.8 mmol·kg −1 . Two amides, 3 and 5 , were selected for evaluation of their inhibitory activity in PLA 2 -induced brain edema and were found to be more potent than dexamethasone after IP administration.

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

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.

Benzamides I, phenylalkanamides II and cinnamamides III are structurally related to the antiinflammatory N-(4,6-dimethylpyridin-2-yl)benzamide I. These were synthesized and the transformation of the 2-aminopyridine nucleus of benzamides I into a 2-imino-1,2-dihydropyridine structure (compounds IV) was also carried out. Of the 49 new derivatives, the 3-fluorobenzamide 9 was the most potent in the oral treatment of carrageenen-induced peripheral edema; IC50 = 12.2 mg·kg−1. It was 3 times as active as benzamide 1, but the latter nevertheless had a better therapeutic index (LD50/IC50) of 52 against 23. Benzamide 1, a non-acidic antiinflammatory compound devoid of any blocking activity on cyclooxygenase, markedly reduces the production of reactive oxygen species in rat peritoneal macrophages. This compound probably acts at the membrane, perhaps by interference with transmembrane events.

Derivatives of 2-amino-4,6-dimethylpyridine resulting from the integration of the amino function into a 2-imidazolidinone were synthetized via the corresponding 2-chloroethylurea. N 3 -benzylation, acylation or sulfonylation afforded the target compounds 6-14 which were evaluated for their in vitro and in vivo antileishmanial activity. Two compounds, the N 3 -benzyl derivative 7 and the N 3 -tolylsulfonyl derivative 14, exhibited potent inhibition against cultured extracellular promastigotes of Leishmania mexicana with IC 50 comparable to that of the previously studied N-(4,6-dimethylpyridin-2-yl) furan-2-carboxamide 2: 32.4, 46 and 69 µmol/l, respectively. Experimentation of their activity against mice macrophage amastigotes pointed out that IC 50 of imidazolidones 7 and 14 were 7 and 13-fold lower than that of amide 2: 13.7 and 89 µmol/l. In vivo evaluation in Balb/c mice, intradermally infested with Leishmania mexicana, confirmed that, in the lesion site, compound 14 was able to significantly reduce the parasite burden at a daily i.p. dose of 10 mg/kg. It was demonstrated that these N-pyridinylimidazolidinones could act by interference with the parasite PLA 2 activity.

The inhibition of the carragenin-induced rat-paw edema by previously synthesized N-(4,6-dimethyl)-2-pyridinyl) benzamides was evaluated. Among the 29 tested compounds, secondary benzamides 1, 12 and tertiary benzamide 60 exhibited a significant anti-inflammatory activity. It prompted us to envision a pharmacomodulation in this series by structural modifications on the homocycle, the amide function and the heterocycle. Although benzamide 38, acetamide 50 and benzylamine 56 elicited marked inhibitory activity, none was more active than N-(4,6-dimethyl-2-pyridinyl) benzamide 1. The mechanism of the anti-inflammatory action of 1 was investigated. The results showed that this molecule reduced eicosanoid biosynthesis but was unable to reduce cyclooxygenase or lipoxygenase activities. Although it did not directly block phospholipase activity, however, an inhibitory process at this level is likely.

Two 3-(alpha-azolylbenzyl)indoles were evaluated against Leishmania amastigotes. Both compounds proved to be very active against intracellular and axenic amastigotes. The IC50 values of the imidazole derivative, PM17, and the triazole analogue, PM19, against L. mexicana axenic amastigotes, were 4.4 +/- 0.1 and 6.4 +/- 0.1 microM, respectively. Against intracellular amastigotes, PM17 produced a 66% decrease of leishmanial burden at 1 microM and PM19 had an IC50 of 1.3 microM. In a Balb/c mice model of L. major leishmaniasis, administration of PM17 led to a clear-cut parasite burden reduction: 98.9% in the spleen, 79.0% in the liver and 49.9% in the popliteal node draining the cutaneous lesion. As anticipated, it was brought to the fore that PM17 decreases ergosterol biosynthesis leading to membrane fungal cell alterations. Moreover it was proved that this imidazole antifungal agent induces a parasite burden-correlated decrease in interleukine-4 production both in the splenocyte and the popliteal node of the mouse.

New N1-mono and N1, N2-disubstituted imidazolidin-2-one with a significant immunosuppressive activity have been discovered. Among the 17 synthesized and tested compounds, five of them showed maximal inhibition of proliferation of concanavallin A (Con A)- stimulated splenocytes at 90 microM, identical to that obtained with cyclosporin A (CsA) at 5 microM, an optimal concentration.

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.

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

A new 2-(alpha-azolylbenzyl)indole derivative exhibited high in vitro activity against 10 strains of Aspergillus fumigatus. This active compound, MT18n, had MIC of 2 microg/mL and is slightly less active than itraconazole and amphotericin B. The mechanism of action of this compound was evaluated through scanning electron microscopy, ergosterol biosynthesis inhibition and phospholipase A2-like activity inhibition studies. Scanning electron microscopy allowed observation of the membrane perturbations caused by MT18n and inference of a critical role of MT18n in membrane synthesis inhibition. Like other azole derivatives MT18n inhibits ergosterol biosynthesis, with a minimal inhibitory concentration of 6 microM. On the other hand, MT18n (10 microM) decreased the secreted phospholipase A2-like activity of Aspergillus fumigatus, an enzyme involved in the invasion process of the host. These results show the high in vitro activity of MT18n against Aspergillus fumigatus and suggest that this compound disturbs the membrane structure via ergosterol biosynthesis inhibition and exhibits phospholipase activity inhibition.

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

Derivatives of 2-amino-4,6-dimethylpyridine resulting from the integration of the amino function into a 2-imidazolidinone were synthetized via the corresponding 2-chloroethylurea. N 3 -benzylation, acylation or sulfonylation afforded the target compounds 6-14 which were evaluated for their in vitro and in vivo antileishmanial activity. Two compounds, the N 3 -benzyl derivative 7 and the N 3 -tolylsulfonyl derivative 14, exhibited potent inhibition against cultured extracellular promastigotes of Leishmania mexicana with IC 50 comparable to that of the previously studied N-(4,6-dimethylpyridin-2-yl) furan-2-carboxamide 2: 32.4, 46 and 69 µmol/l, respectively. Experimentation of their activity against mice macrophage amastigotes pointed out that IC 50 of imidazolidones 7 and 14 were 7 and 13-fold lower than that of amide 2: 13.7 and 89 µmol/l. In vivo evaluation in Balb/c mice, intradermally infested with Leishmania mexicana, confirmed that, in the lesion site, compound 14 was able to significantly reduce the parasite burden at a daily i.p. dose of 10 mg/kg. It was demonstrated that these N-pyridinylimidazolidinones could act by interference with the parasite PLA 2 activity.

C 26 H 34 N 2 O 2 cristallise dans P2 1 /n avec a=7.941, b=17.036, c=17.841A, β=101.61°, Z=4; affinement jusqu'a R=0.041. Les trois cycles sont plans ou presque plans. Exceptes les atomes C terminaux des deux substituants t-butyl, la molecule est approximativement plane. Dans le cycle pyrrolidine existe une orbitale delocalisee sur la chaine C-N-O. Les trois liaisons comprises entre le cycle pyridine, la chaine C-N-O, la liaison ethylenique et le cycle benzenique ont un caractere partiel π

2 C 16 H 16 N 2 O•H 2 O cristallise dans P2 1 /n avec a=14,208, b=14,764, c=28,592 A, β=103,76 o , Z=8; affinement jusqu'a R=0,044. Les longueurs et les angles des liaisons sont en accord avec ceux obtenus pour des composes analogues. Les 4 molecules organiques dans la maille asymetrique ont des geometries similaires. Chacune d'elles est approximativement plane avec une orbitale delocalisee au-dessus du groupement amide

Derivatives of 2-amino-4,6-dimethylpyridine, aryl(alkyl)carboxamides, thiocarbamides and amidra-zones, 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 Alzheimer's disease.

Resume Des hydroxy-2 indanediones-1,3 3 , diversement substituees sur l'heterocycle, ont ete preparees et experimentees vis-a-vis de l'œdeme a la carragenine chez la Souris. L'hydrogenation catalytique de ces hydroxy β-dicetones conduit aux dihydroxy-2,3 indanones 6 tandis que la reduction de 3i par le borohydrure de sodium fournit l'indanetriol 7i . Elles subissent, en milieu alcalin, une isomerisation en indolylcarbonyl-3 phtalides 9 . Seul le compose, 3d exerce une inhibition significative de l'œdeme; cette activite a ete confirmee dans le modele de l'œdeme chez le Rat, mais elle s'accompagne d'une activite anti-coagulante. On constate que la presence d'enchainements ω-aminoalkyles sur l'azote indolique de 3d entraine la disparition de l'activite anti-inflammatoire. Bien que structuralement proches des γ-pyrophtalones actives anterieurement etudiees, les (indolyl-3 methylene)-2 indanediones-1,3 12 ne manifestent pas d'activite anti-inflammatoire.