The synthesis and structure-activity relationships of novel 4-(4 '-fluorophenyl)imidazoles as selective p38 alpha MAPK, CK1 delta and JAK2 inhibitors with improved water solubility are described. Microwave-assisted multicomponent reactions afforded 4-fluorophenyl-2,5-disubstituted imidazoles. Carboxylate and phosphonate groups were introduced via 'click' reactions. The kinase selectivity was influenced by the heteroaryl group at imidazole C-5 and the position of a carboxylic acid or tetrazole at imidazole C-2. For example, pyrimidines 15 and 34 inhibited p38 alpha MAPK with IC50 = 250 nM and 96 nM, respectively. Pyridine 3 gave CK1 delta inhibition with IC50 = 89 nM and pyridin-2-one 31 gave JAK2 inhibition with IC50 = 62 nM. (C) 2014 Elsevier Ltd. All rights reserved.
- p38 alpha MAPK, CK1 delta, JAK2 inhibitors
- Multicomponent reactions
- Alkyne-azide click reaction
- Aqueous solubility
- ACTIVATED PROTEIN-KINASE