2. Academic Validation
  3. Novel multitarget 5-arylidenehydantoins with arylpiperazinealkyl fragment: Pharmacological evaluation and investigation of cytotoxicity and metabolic stability

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

  • Bioorg Med Chem. 2019 Sep 15;27(18):4163-4173. doi: 10.1016/j.bmc.2019.07.046.
Anna Czopek 1,  Adam Bucki 2,  Marcin Kołaczkowski 2,  Agnieszka Zagórska 2,  Marcin Drop 2,  Maciej Pawłowski 2,  Agata Siwek 3,  Monika Głuch-Lutwin 3,  Elżbieta Pękala 4,  Alicja Chrzanowska 5,  Marta Struga 5,  Anna Partyka 6,  Anna Wesołowska 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland. Electronic address: anna.czopek@uj.edu.pl.
  • 2 Department of Pharmaceutical Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
  • 3 Department of Pharmacobiology, Jagiellonian University Collegium Medicum, Krakow, Poland.
  • 4 Department of Pharmaceutical Biochemistry, Jagiellonian University Collegium Medicum, Krakow, Poland.
  • 5 Chair and Department of Biochemistry, Medical University, 02-097 Warszawa, Poland.
  • 6 Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
PMID: 31383628 DOI: 10.1016/j.bmc.2019.07.046
Abstract

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-HT1A and 5-HT7 receptors (Ki = 0.2-1.0 nM) but a negligible inhibitory effect on PDE4. The high affinity of the compounds for 5-HT1A 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-HT1A and 5-HT7 receptor antagonists and exhibited antidepressant-like activity, similar to the reference drug citalopram, in an animal model of depression.

Keywords

5-HT(1A)/5-HT(7) modulators; Antidepressant activity; Cytotoxicity; Hydantoin; PDE4 inhibitors.

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