We report an extensive structure-activity relationship optimization of polysubstituted pyrimidines that led to the discovery of 5-butyl-4-(4-benzyloxyphenyl)-6-phenylpyrimidin-2-amine, and its difluorinated analogue. These compounds are sub-micromolar inhibitors of PGE2 production (IC50 as low as 12 nM). In order to identify the molecular target of anti-inflammatory pyrimidines, we performed extensive studies including enzymatic assays, homology modeling and docking. The difluorinated analogue simultaneously inhibits two key enzymes of the arachidonic acid cascade, namely mPGES-1 and COX-2, with mPGES-1 inhibition being the principal mechanism of action. Other pyrimidines studied are potent mPGES-1 inhibitors with no observed inhibition of COX-1/2 enzymes. Moreover, the two most potent compounds proved to be significantly effective in vivo in a model of acute inflammation, suppressing carrageenan-induced rat paw edema by 36 and 46 %. The promising results of this study warrant further preclinical evaluation of selected anti-inflammatory candidates.
- MeSH
- antiflogistika nesteroidní aplikace a dávkování chemie farmakologie MeSH
- aplikace orální MeSH
- buněčné linie MeSH
- dinoproston antagonisté a inhibitory biosyntéza MeSH
- edém chemicky indukované farmakoterapie MeSH
- karagenan MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši MeSH
- objevování léků MeSH
- pyrimidiny aplikace a dávkování chemie farmakologie MeSH
- syntázy prostaglandinu E antagonisté a inhibitory metabolismus MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
As a part of a broader structure-activity relationship study of substituted 2-aminopyrimidines, the influence of the C-5 substitution on inhibition of prostaglandin E2 (PGE2) production was studied. Thirty compounds were prepared starting from the corresponding 2-amino-4,6-dichloropyrimidines using Suzuki cross-coupling. It was shown previously that 2-amino-4,6-dichloropyrimidines with smaller C-5 substituent (hydrogen and methyl) were devoid of significant activity, while 5-butyl derivatives exhibited prominent potency. In this study, on the other hand, both monoaryl- and bisarylpyrimidines were potent inhibitors of PGE2 production regardless the length of the C-5 substituent (hydrogen, methyl, n-butyl). Moreover, the shorter the C-5 substituent the higher potency to inhibit PGE2 production was observed. 2-Amino-4,6-diphenylpyrimidine was the best inhibitor of PGE2 production with IC50 = 3 nM and no cytotoxicity. The most potent inhibitors deserve further preclinical evaluation as potential anti-inflammatory agents.
- MeSH
- antiflogistika nesteroidní chemická syntéza chemie farmakologie MeSH
- biosyntetické dráhy účinky léků MeSH
- dinoproston antagonisté a inhibitory metabolismus MeSH
- kultivované buňky MeSH
- myši inbrední C57BL MeSH
- pyrimidiny chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Certain non-steroidal anti-inflammatory drugs can inhibit fungal growth, fungal prostaglandin E2 production, and enzyme activation. This study aims to investigate the antifungal effect of nimesulide against pathogenic filamentous fungi and yeast. The experiments detailed below were also designed to investigate whether the action is dependent on E2 fungal prostaglandins. Our data showed that nimesulide exhibited potent antifungal activity, mainly against Trichophyton mentagrophytes (ATCC 9533) and Cryptococcus neoformans with MIC values of 2 and 62 μg/mL, respectively. This drug was also able to inhibit the growth of clinic isolates of filamentous fungi, such as Aspergillus fumigatus, and dermatophytes, such as T. rubrum, T. mentagrophytes, Epidermophyton floccosum, Microsporum canis, and M. gypseum, with MIC values ranging from 112 to 770 μg/mL. Our data also showed that the inhibition of fungal growth by nimesulide was mediated by a mechanism dependent on PGE2, which led to the inhibition of essential fungal enzymes. Thus, we concluded that nimesulide exerts a fungicidal effect against pathogenic filamentous fungi and yeast, involving the inhibition of fungal prostaglandins and fungal enzymes important to the fungal growth and colonization.
- MeSH
- antifungální látky farmakologie MeSH
- Arthrodermataceae účinky léků růst a vývoj metabolismus MeSH
- Aspergillus fumigatus účinky léků růst a vývoj metabolismus MeSH
- Cryptococcus neoformans účinky léků růst a vývoj metabolismus MeSH
- dinoproston antagonisté a inhibitory biosyntéza MeSH
- mikrobiální testy citlivosti MeSH
- sulfonamidy farmakologie MeSH
- Trichophyton účinky léků růst a vývoj metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
As a part of our extensive structure-activity relationship study of anti-inflammatory heterocycles, a novel series of 67 polysubstituted 2-aminopyrimidines was prepared bearing one (at the C-4 position of the pyrimidine ring) or two (in the C-4 and C-6 positions) (hetero)aryl substituents attached directly through the C-C bond. The key synthetic steps involved either Suzuki-Miyaura or Stille cross-coupling reactions carried out on easily available 4,6-dichloropyrimidines. All prepared compounds, except one, were able to inhibit immune-activated production of nitric oxide (NO) significantly. Moreover, several compounds were found to be low micromolar dual inhibitors of NO and prostaglandin E2 (PGE2) production. Although the exact mode of action of the prepared compounds remains to be elucidated, non-toxic dual inhibitors of NO and PGE2 production may have great therapeutic benefit in treatment of various inflammation diseases and deserve further preclinical evaluation.
The present in vitro experiments demonstrate inhibitory effects of polysubstituted 2-aminopyrimidines on high output production of nitric oxide (NO) and prostaglandin E2 (PGE2) stimulated by interferon-γ and lipopolysaccharide (LPS) in peritoneal macrophages of mouse and rat origin. PGE2 production was inhibited also in LPS-activated human peripheral blood mononuclear cells. A tight dependence of the suppressive activities on chemical structure of pyrimidines was observed. Derivatives containing hydroxyl groups at the C-4 and C-6 positions of pyrimidine ring were devoid of any influence on NO and PGE2. Remarkable inhibitory potential was acquired by the replacement of hydroxyl groups with chlorine, the 4,6-dichloro derivatives being more effective than the monochloro analogues. The effects were further intensified by modification of the amino group at the C-2 position, changing it to the (N,N-dimethylamino)methyleneamino or the formamido ones. There was no substantial difference in the expression of NO-inhibitory effects among derivatives containing distinct types of substituents at the C-5 position (hydrogen, methyl, ethyl, propyl, butyl, phenyl, and benzyl). In contrast to NO, larger substituents then methyl were required to inhibit PGE2 production. Overall, no significant correlation between the extent of NO and PGE2 suppression was observed. The IC50s of derivatives with the strongest effects on both NO and PGE2 were within the range of 2-10 μM. Their NO-inhibitory potential of pyrimidines was stronger than that of non-steroidal anti-inflammatory drugs (NSAIDs) aspirin and indomethacin. The PGE2-inhibitory effectiveness of pyrimidines was about the same as that of aspirin, but weaker as compared to indomethacin. The NO- and PGE2-inhibitory activity of tested pyrimidines has been found associated with decreased expression of iNOS mRNA and COX-2 mRNA, respectively, and with post-translation interactions. Selected NO-/PGE2-inhibitory derivatives decreased severity of intestinal inflammation in murine model of ulcerative colitis.
- MeSH
- antiflogistika nesteroidní aplikace a dávkování farmakologie MeSH
- Aspirin farmakologie MeSH
- cyklooxygenasa 2 genetika metabolismus MeSH
- dinoproston antagonisté a inhibitory biosyntéza MeSH
- indomethacin farmakologie MeSH
- interferon gama farmakologie MeSH
- kolon účinky léků metabolismus MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- messenger RNA metabolismus MeSH
- mitogenem aktivované proteinkinasy metabolismus MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- oxid dusnatý antagonisté a inhibitory biosyntéza MeSH
- peritoneální makrofágy účinky léků metabolismus MeSH
- potkani inbrední LEW MeSH
- pyrimidiny aplikace a dávkování farmakologie MeSH
- synthasa oxidu dusnatého, typ II genetika metabolismus MeSH
- ulcerózní kolitida farmakoterapie patofyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We investigated the role of prostaglandin E2 in reptilian regeneration. Prostaglandin E2 is known to play a vital role during wound healing and cell proliferation. A significant delay in the rate of growth of regenerate after autotomy was observed when the production of prostaglandin E2 was blocked by usage of specific cyclooxygenase inhibitors as compared to control animals and this delay continued to all the defined stages of regeneration. Therefore, prostaglandin E2 could be one of the essential requirements for a successful process of regeneration.
- MeSH
- cyklooxygenasa 2 biosyntéza MeSH
- dinoproston antagonisté a inhibitory fyziologie MeSH
- inhibitory cyklooxygenasy farmakologie MeSH
- ještěři fyziologie MeSH
- ocas fyziologie účinky léků MeSH
- pyrazoly farmakologie MeSH
- pyridiny farmakologie MeSH
- regenerace fyziologie účinky léků MeSH
- sulfonamidy farmakologie MeSH
- sulfony farmakologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
