Abstract
An alternative strategy for the synthesis of 1-aryl- and 1-alkyl-2-methylsulfanyl-4-(4-fluorophenyl)-5-(pyridin-4-yl)imidazoles as potential p38α mitogen-activated protein kinase inhibitors is reported. The regioselective N-substitution of the imidazole ring was achieved by treatment of α-aminoketones with different aryl or alkyl isothiocyanates. In contrast to previously published synthesis routes starting from 2-amino-4-methylpyridine, the presented route is characterized by a higher flexibility and a lower number of steps. This strategy was also applied to access 1-alkyl-2-methylsulfanyl-5-(4-fluorophenyl)-4-(pyridin-4-yl)imidazoles in six steps starting from 2-chloro-4-methylpyridine.
Highlights
The p38α mitogen-activated protein (MAP) kinase is a serine/threonine kinase, which plays a role in signal transduction pathways, modulating the cellular response to external stress stimuli like infection, heat or osmotic shock, UV light, and inflammatory cytokines [1]
Through phosphorylation of multiple downstream targets, this kinase triggers a wide range of cellular processes mostly resulting in the stimulation of the inflammatory reaction [1,2]
Several studies suggested that the p38α MAP kinase may play a role as a major character in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis [5,6,7,8]
Summary
The p38α mitogen-activated protein (MAP) kinase is a serine/threonine kinase, which plays a role in signal transduction pathways, modulating the cellular response to external stress stimuli like infection, heat or osmotic shock, UV light, and inflammatory cytokines [1]. Several studies suggested that the p38α MAP kinase may play a role as a major character in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis [5,6,7,8]. Due to this well-documented physiopathological role, inhibition of the p38α MAP kinase has been widely pursued in many medicinal chemistry programs [9,10]. 50 data from our research group; compounds tested in as p38α MAP kinase inhibitors.
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