Preparation of new hydroxycoumarin derivatives with potential activity towards serotonergic receptors

The project involves the production of a series of new chemical compounds, hydroxycoumarin derivatives, with high affinity for serotonergic receptors and the serotonin transporter. Compounds were designed based on a literature review and using molecular modeling methods. The structures of the compounds were planned on the basis of the previous research in which a pilot series of aryl-piperazinyl-propoxyl and butoxy derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin was obtained, their activity profile and affinity for some serotoninergic receptors were determined. Initial results are optimistic and encourage further research. It was found that the introduction of an acetyl group at the 8-position of the coumarin ring contributed to a significant increase in affinity for the 5-HT1A receptor (Ki = 89.2 nM for the compound without an acetyl group to Ki = 0.8 nM for 8-acetyl-7- {4 - [4- (3-methoxyphenyl) -1-piperazinyl] butoxy} -4-methyl coumarin). Moreover, due to molecular docking, it was found that compounds of this type are stabilized in the receptor pocket mainly by the hydrogen bond between Ser190 and the acetyl group of coumarin. This binding has previously been reported to be important in the binding of (non-coumarin) ligands to the 5-HT1A receptor. Also important is the substitution of the 4-position on the coumarin ring with a methyl group and, of course, the selection of the appropriate linker and arylpiperazine derivatives having substituents in the ortho or ortho / meta position of the phenyl ring. Based on the above data, I decided to synthesize new arylpiperazinyl derivatives of hydroxycoumarins with the use of a three / four / five and six carbon linker and a number of amines. Organic synthesis is based on certain and proven chemical reactions. The compounds planned under the project will be obtained as a result of multistage organic syntheses, mostly with the use of a microwave reactor. The derivatives will be purified by crystallization or column chromatography methods, and their structures will be confirmed by1H NMR, 13C NMR, MS spectra, and by crystallographic methods for selected molecules. The main result of the presented project will be the purification and confirmation of the structures of planned chemical compounds with the expected pharmacological activity. The results will be published in international journals. We envisage the preparation of aryl-piperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin and 6-acetyl-5-hydroxy-4,7-dimethylcoumarin containing an acetyl group in ortho position to the coumarin hydroxyl group. The aryl piperazinyl derivatives of 5-hydroxycoumarin have never been described in the scientific literature or tested in terms of affinity to serotonin receptors. The project will allow to enrich the library of coumarin derivatives with new derivatives, and the obtained results will constitute the material of the project manager's habilitation dissertation. As the project is part of the medical chemistry framework, pharmacological tests will be necessary (apart from the presented application). The affinity for serotonergic receptors and the serotonin transporter will be determined based on in vitro studies (as part of scientific cooperation with the Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University).