Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HT_1A Serotonin Receptor Antagonists

• Main Authors: Kinga Ostrowska, Anna Leśniak, Zuzanna Czarnocka, Jagoda Chmiel, Magdalena Bujalska-Zadrożny, Bartosz Trzaskowski
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Pharmaceuticals
• Subjects: molecular docking; microwave-assisted synthesis; hydroxycoumarin derivatives; 5-HT_1A; 5-HT_2A; receptors ligands
• Online Access: https://www.mdpi.com/1424-8247/14/3/179

We have designed and synthesized a series of 60 new 5- and 7-hydroxycoumarin derivatives bearing the piperazine moiety with the expected binding to 5-HT_1A and 5-HT_2A receptors. Molecular docking of all investigated compounds revealed subnanomolar estimates of 5-HT_1AR K_ifor three ligands and 5-HT_2AR Ki for one ligand as well as numerous low nanomolar estimates of K_ifor both receptors. Intrigued by these results we synthesized all 60 new derivatives using microwave-assisted protocols. We show that three new compounds show a relatively high antagonistic activity against the 5HT_1A receptor, although lower than the reference compound WAY-100635. These compounds also showed relatively low binding affinities to the 5-HT_2A receptor. We also provide a detailed structure–activity analysis of this series of compounds and compare it with previously obtained results for an exhaustive series of coumarin derivatives.