Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HT1A Serotonin Receptor Antagonists

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-HT1A and 5-HT2A receptors. Molecular docking of all investigated compounds revealed subnanomolar estimates of 5-HT1AR K-i for three ligands and 5-HT2AR Ki for one ligand as well as numerous low nanomolar estimates of K-i for 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-HT2A 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.

Automated summary

A series of 60 new 5- and 7-hydroxycoumarin derivatives with the piperazine moiety were designed and synthesized for potential binding to 5-HT1A and 5-HT2A receptors. Molecular docking indicated subnanomolar estimates of Ki values for some ligands, and microwaved-assisted protocols were used for synthesis. Three compounds showed relatively high antagonistic activity against the 5HT(1A) receptor, with lower affinities towards the 5-HT2A receptor.