Exploring the Synthesis of New 1-(4-Substitutedphenylamino) imidazo[1,5-a]indol-3-one Derivatives as Cyclized Analogs of Leucettines

Guillaume Burgy (1, 2) , Emmanuelle Limanton (2) , François Carreaux (2) , Emilie Durieu (1) , Laurent Meijer (1) , Jean-Pierre Bazureau (2)

1 ManRos Therapeutics
2 ISCR - Institut des Sciences Chimiques de Rennes

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).

Keywords: imidazo[1; 5-a]indol-3-one; thiourea; isothiorurea; intramolecular; sulphur/ nitrogen displacement; protein kinase; DYRKs; CLKs; Leucettines

Domains: Chemical Sciences; Life Sciences [q-bio]; Pharmaceutical sciences

Guillaume Burgy, Emmanuelle Limanton, François Carreaux, Emilie Durieu, Laurent Meijer, et al.. Exploring the Synthesis of New 1-(4-Substitutedphenylamino) imidazo[1,5-a]indol-3-one Derivatives as Cyclized Analogs of Leucettines. Journal of Applied Pharmaceutical Science, 2014, 4 (6), pp.25 - 32. ⟨10.7324/JAPS.2014.40604⟩. ⟨hal-01116022⟩