Abstract

Glycogen synthase kinase 3 (GSK-3) has become known for its multifactorial involvement in the pathogenesis of Alzheimer's disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3 (4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3 beta, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 +/- 0.023 mu M) and halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 +/- 0.060 mu M) displayed high GSK-3 beta inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50 = 0.072 +/- 0.043) in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3 beta, since a targeted interaction might provide improved kinase-selectivity.