Novel 4,5‐Dihydrothiazole‐Phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents
The synthesis of a new series of long-chain arylpiperazine as serotoninergic ligands (FG 1-18) is described. The combination of structural elements including heterocyclic nucleus, propyl chain, and 4,5-dihydrothiazol-2-ylphenylpiperazines leads to the preparation of different derivatives tested for their affinity toward 5-HT<sub>1A</sub>, 5-HT<sub>2A</sub>, and 5-HT<sub>2C</sub> receptors. The compounds with better affinity and selectivity binding profiles toward 5-HT<sub>1A</sub> and 5-HT<sub>2C</sub> (FG-1, FG-4, FG-5, FG-6, FG-7, FG-8, and FG-18) are selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies are performed. The results of pharmacological studies show that compounds FG-1, FG-5, FG-8, and FG-6 exert antidepressant-like effects, and FG-1, FG-18, FG-6, and FG-7 reveal also significant anxiolytic properties. Among the developed derivatives, the most promising compounds seem to be FG-1, which exhibit antidepressant, anxiolytic, and anticonvulsant properties, FG-7 and FG-18 that show features as anxiolytic combine to a pro-cognitive property and notable affinity and selectivity for 5-HT<sub>2C</sub> receptor, respectively.
Authors
- Vincenzo Santagada (ORCID: https://orcid.org/0000-0001-8377-8990)
- Jolanta Helena Kotlinska (ORCID: https://orcid.org/0000-0002-4178-1515)
- Grażyna Biała (ORCID: https://orcid.org/0000-0001-8270-9635)
- Ferdinando Fiorino (ORCID: https://orcid.org/0000-0001-7357-5751)
- Beatrice Ulloa Severino (ORCID: https://orcid.org/0000-0002-3887-8869)
- Anna Bielenica (ORCID: https://orcid.org/0000-0003-3269-9672)
- Ewa Kędzierska (ORCID: https://orcid.org/0000-0002-2648-6075)
- Elisa Magli (ORCID: https://orcid.org/0000-0002-9930-9467)
- Rosa Sparaco (ORCID: https://orcid.org/0009-0003-4221-5560)
- Angela Corvino (ORCID: https://orcid.org/0000-0002-0617-156X)
- Giuseppe Caliendo (ORCID: https://orcid.org/0000-0002-5098-6045)
- Agnieszka A. Kaczor (ORCID: https://orcid.org/0000-0001-8679-9623)
- Raffaele Capasso (ORCID: https://orcid.org/0000-0002-3335-1822)
- Nataliia Semenko (ORCID: https://orcid.org/0000-0001-8235-386X)
- Anna Leśniak (ORCID: https://orcid.org/0000-0002-6014-9208)
- Ewa Gibuła‐Tarłowska (ORCID: https://orcid.org/0000-0001-7791-0633)
- Kinga Gaweł (ORCID: https://orcid.org/0000-0001-8857-847X)
- Natalia Karkoszka
- Giorgia Andreozzi
Institutions
- Medical University of Lublin (PL)
- University of Eastern Finland (FI)
- Medical University of Warsaw (PL)
- Department of Agricultural Sciences (RU)
- University of Naples Federico II (IT)
- Bogomolets National Medical University (UA)
Publication Details
- Journal
- ChemMedChem
- Published
- 2025-06-03
- DOI
- https://doi.org/10.1002/cmdc.202500288
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Università degli Studi di Napoli Federico II
- Uniwersytet Medyczny w Lublinie