# Novel 4,5‐Dihydrothiazole‐Phenylpiperazine Derivatives: Synthesis, Docking Studies and Pharmacological Evaluation as Serotonergic Agents

## TL;DR

This paper describes the synthesis and testing of new serotonin-related compounds that show antidepressant, anxiolytic, and pro-cognitive effects.

## Contribution

The paper introduces novel 4,5-dihydrothiazole-phenylpiperazine derivatives with serotonin receptor activity and potential therapeutic properties.

## Key findings

- Compounds FG-1, FG-5, FG-8, and FG-6 show antidepressant-like effects.
- FG-1, FG-18, FG-6, and FG-7 exhibit significant anxiolytic properties.
- FG-7 and FG-18 demonstrate notable pro-cognitive and 5-HT2C receptor selectivity.

## Abstract

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.

The synthesis of a new series of 4,5‐dihydrothiazol‐2‐ylphenylpiperazine derivatives as serotoninergic ligands is described and tested for their affinity toward 5‐HT1A, 5‐HT2A,and 5‐HT2C and selected for further in vivo assays to determine their functional activity. The pharmacological studies highlight that among the developed derivatives, FG‐7 and FG‐18 show notable features as anxiolytic combine to pro‐cognitive property.© 2025 WILEY‐VCH GmbH