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-HT1A, 5-HT2A, and 5-HT2C receptors. The compounds with better affinity and selectivity binding profiles toward 5-HT1A and 5-HT2C (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-HT2C receptor, respectively.