Three series of substituted 2-alkylsulfanyl-4-(4-fluorophenyl)imidazoles, 5-pyridinyl-, 1-methyl-5-pyridinyl-, and 5-(2-aminopyridin-4-yl)-imidazoles, were prepared and tested for their ability to inhibit p38 MAP kinase and TNF-alpha release. These compounds were prepared by using different synthetic routes. They were tested by applying a nonradioactive p38 MAP kinase assay and by measurement of TNF-alpha release in human whole blood. Potent inhibitors (IC50 values in the low nanomolar range, as low as 2 nM in the enzyme assay and 37 nM in the human whole blood test) were identified by variation of substituents at the imidazole- C2-thio position as well as at the 2-aminopyridinyl functionality. In contrast to other known kinase inhibitors, these novel imidazole derivatives with the substituents at the imidazole-C2-thio position may interact with the ribose as well as with the phosphate binding site of the p38 MAP kinase.

Two routes to the deoxydisaccharide angucycline antibiotic 100-1 (3) are described. Key steps comprise the regioselective oxidation/bromination of the 1,5-diacetoxyolivose C-saccharide 7 to the bromoquinone 8. Diels -Alder reaction of the bromoquinone with the diene 9 followed by HBr elimination afforded the urdamycinone B precursor 11 as a diastereomeric mixture. Selective protection as the TBDMS ether 13, acetylation and deprotection of the silyl ether afforded the alcohol 15 which was selectively glycosylated to the a-rhamnal glycoside 17 in 72% yield (at 70% conversion) using benzoyl rhamnal (16) as the glycoside donor and scandium triflate as the promotor. The silyl group at C-3 of the aglycone was then transformed into a hydroxyl group. Zemplén deacylation and photooxidation of the benzylic position at C-1 then converted the two diastereoisomers into the natural product 3 and the C-3 diastereoisomer 20. At this stage the diastereomers 3 and 20 were separated. Alternatively and more easily, the diastereomers were separated at the stage of the urdamycinone B analogues 21a and 21b, followed by a similar reaction sequence to the natural disaccharide 3.

Methods for the construction of naphthalene oligodeoxy disaccharide fragments, common structural elements of the angucycline antibiotics, are investigated. The triphenylphosphonium bromide-or scandium triflate-catalyzed addition of rhodinal to 4-OH silyl-protected olivoses affords the required 3-Ocx-oligodeoxy disaccharides selectively and in high yields.

The title compound, C19H18FN3O2S, was synthesized in the course of studies on 2-alkyl­sufanylimidazoles as p38 mitogen-activated protein kinase inhibitors. The synthesis was achieved by nucleophilic substitution of 4-(4-fluoro­phen­yl)-5-(pyridin-4-yl)-1,3-dihydro­imidazole-2-thione with methyl 4-bromo­butanoate. The five-membered heterocycle makes dihedral angles of 32.4 (2) and 18.3 (2)° with the fluoro­phenyl and pyridinyl rings, respectively, indicating a low degree of conjugation between these rings. Intra­molecular C—H⋯N and inter­molecular N—H⋯N hydrogen bonds as well as C—H⋯π inter­actions seem to be effective in stabilization of the crystal structure.

No abstract