New 1-arylaminoimidazo[1,5-a]indol-3-ones were synthesized as cyclized derivatives of leucettine L41, a low molecular weight inhibitor of the DYRKs/CLKs protein kinases with potential applications in Alzheimer's disease and Down syndrome. In this first approach, access to the desired 1-aminoimidazo[1,5-a]indol-3-ones involved 5 steps and was explored with a series of various primary amines and polar secondary amines in order to introduce molecular diversity on N-1 position. The 5 step synthesis of the 1-arylaminoimidazo[1,5-a]indol-3-ones was achieved and the limiting step of this process was the final cyclization via a sulphur/nitrogen displacement from methylsulfanyl thiourea intermediates. Good results were obtained for isothioureas derived from primary amines. The 1-arylaminoimidazo[1,5-a]indol-3-ones were evaluated on a panel of five protein kinases (DYRK1A, CK1, CDK5/p25, GSK3α/β and CLK1).
Key words: imidazo[1,5-a]indol-3-one, thiourea, isothiorurea, intramolecular sulphur/nitrogen displacement, protein kinase, DYRKs, CLKs, Leucettines.
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