New 5-Aryl-Substituted 2-Aminobenzamide-Type HDAC Inhibitors with a Diketopiperazine Group and Their Ameliorating Effects on Ischemia-Induced Neuronal Cell Death.

We previously synthesized new 5-thienyl-substituted 2-aminobenzamide-type HDAC1, 2 inhibitors with the (4-ethyl-2,3-dioxopiperazine-1-carboxamido) methyl group. K-560 (1a) protected against neuronal cell death in a Parkinson's disease model by up-regulating the expression of XIAP. This finding prompted us to design new K-560-related compounds. We examined the structure activity relationship (SAR) for the neuronal protective effects of newly synthesized and known K-560 derivatives after cerebral ischemia. Among them, K-856 (8), containing the (4-methyl-2,5-dioxopiperazin-1-yl) methyl group, exhibited a promising neuronal survival activity. The SAR study strongly suggested that the attachment of a monocyclic 2,3- or 2,5-diketopiperazine group to the 2-amino-5-aryl (but not 2-nitro-5-aryl) scaffold is necessary for K-560-related compounds to exert a potent neuroprotective effect.