Design, synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 13; pp. 3773 - 3784
• Main Authors: Kubacka, M., Szkaradek, N., Mogilski, S., Pańczyk, K., Siwek, A., Gryboś, A., Filipek, B., Żmudzki, P., Marona, H., Waszkielewicz, A.M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 30.07.2018
• Subjects: Adrenergic Antagonists - chemical synthesis; Adrenergic Antagonists - metabolism; Adrenergic Antagonists - pharmacology; Adrenoceptor; Animals; Arrhythmia; Blood Pressure - drug effects; Calcium Channel Blockers - chemical synthesis; Calcium Channel Blockers - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels - chemistry; Calcium Channels - metabolism; Cardiovascular; Drug Design; Heart Rate - drug effects; Hypertension; Inhibitory Concentration 50; Male; Platelet Aggregation - drug effects; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, alpha - chemistry; Receptors, Adrenergic, alpha - metabolism; Receptors, Adrenergic, beta - chemistry; Receptors, Adrenergic, beta - metabolism; Structure-Activity Relationship; Synthesis; Verapamil - chemistry; Xanthone; Xanthones - chemistry; Xanthones - metabolism; Xanthones - pharmacology; Hypertension; Xanthone; Synthesis; Arrhythmia; Cardiovascular; Adrenoceptor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2018.04.038

[Display omitted] •We synthesized 8 derivatives of xanthone with structural elements of known drugs.•We evaluated cardiovascular activity of the tested compounds.•They revealed diversified affinity to adrenoceptors.•In vivo evaluation confirmed their antiarrhythmic and hypotensive potential.•They exerted additional anti-aggregation effect. A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), β-(compounds 1, 3, 4, 7), α1/β-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.