Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability

On the basis of the structures of serotonin modulators or drugs (NAN-190, buspirone, aripiprazole) and phosphodiesterase 4 (PDE4) inhibitors (rolipram, RO-20-1724), a series of novel multitarget 5-arylidenehydantoin derivatives with arylpiperazine fragment was synthesized. Among these compounds, 5-(3,4-dimethoxybenzylidene-3-(4-(4-(2,3-dichlorophenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (13) and 5-(3-cyclopentyloxy-4-methoxybenzylidene-3-(4-(4-(2-methoxyphenyl)piperazine-1-yl)butyl)-imidazolidine-2,4-dione (18) were found to be the most promising showing very high affinity toward 5-HT_1A and 5-HT₇ receptors (K_i = 0.2-1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT_1A and 5-HT₇ receptors was further investigated by computer-aided studies. Moreover, compounds 13 and 18 showed no significant cytotoxicity in the MTT assay, but high clearance in the in vitro assay. In addition, these compounds behaved like 5-HT_1A and 5-HT₇ receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.