Synthesis and evaluation of pharmacological properties of some new xanthone derivatives with piperazine moiety

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 15; pp. 4419 - 4423
• Main Authors: Waszkielewicz, A.M., Gunia, A., Szkaradek, N., Pytka, K., Siwek, A., Satała, G., Bojarski, A.J., Szneler, E., Marona, H.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2013; Elsevier
• Subjects: 1,4-Piperazine derivatives; 5-HT; Administration, Oral; Adrenergic receptors; Animals; Anticonvulsant activity; anticonvulsants; Anticonvulsants - chemical synthesis; Anticonvulsants - pharmacokinetics; Anticonvulsants - therapeutic use; bioavailability; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Evaluation, Preclinical; Electroshock; Epilepsy; Half-Life; Kinetics; Life Sciences & Biomedicine; MES; oral administration; Pharmacology & Pharmacy; Physical Sciences; piperazine; Piperazines - chemistry; Protein Binding; Rats; Receptor, Serotonin, 5-HT1A - chemistry; Receptor, Serotonin, 5-HT1A - metabolism; receptors; Receptors, Serotonin - chemistry; Receptors, Serotonin - metabolism; Science & Technology; Seizures - drug therapy; Serotoninergic receptors; Xanthone; Xanthones - chemistry; Xanthones - pharmacokinetics; Xanthones - therapeutic use; 1,4-Piperazine derivatives; Xanthone; Epilepsy; Anticonvulsant activity; Adrenergic receptors; MES; 5-HT; Serotoninergic receptors; RECEPTOR AFFINITY; ACIDS; NAFTOPIDIL; PRX-00023; 5-HT1A; SURFACE; AGENTS; AGONIST
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2013.05.062

A series of new xanthone derivatives with piperazine moiety [1–7] was synthesized and evaluated for their pharmacological properties. They were subject to binding assays for α1 and β1 adrenergic as well as 5-HT1A, 5-HT6 and 5-HT7b serotoninergic receptors. Five of the tested compounds were also evaluated for their anticonvulsant properties. The compound 3a 3-methoxy-5-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-9H-xanthen-9-one hydrochloride exhibited significantly higher affinity for serotoninergic 5-HT1A receptors (Ki=24nM) than other substances. In terms of anticonvulsant activity, 6-methoxy-2-{[4-(benzyl)piperazin-1-yl]methyl}-9H-xanthen-9-one (5) proved best properties. Its ED50 determined in maximal electroshock (MES) seizure assay was 105mg/kg b.w. (rats, p.o.). Combining of xanthone with piperazine moiety resulted in obtaining of compounds with increased bioavailability after oral administration.