In line with our previous studies, we have developed through a rational design approach novel morpholine and benzoxa(or thia)zine lead compounds that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) interact and scavenge free radicals, b) inhibit the metal ion (Cu2+)-induced LDL oxidation c) act intracellularly as antioxidants in THP- 1 monocytes from a leukemic patient and d) inhibit the pro-inflammatory enzymes cycloxygenase-1 (COX-1) and -2 (COX-2) in vitro. Furthermore, two representative compounds were tested for their potential to decrease lipidemic parameters (TC, LDL and TG) in hyperlipidemic mice. Most derivatives indicated a remarkable antioxidant activity, while at the same time exhibited a significant in vitro anti-inflammatory activity, inhibiting COX-1 or/and COX-2 activity at 20 μΜ. Furthermore, after their long-term administration, compounds 6 and 8 afforded a considerable activity in a chronic experimental animal model of hyperlipidemia (after high fat diet administration). The multifunctional pharmacological profile exhibited by the compounds of this study renders them interesting lead compounds for the development of novel agents against atherosclerosis.

Matralis, A., Bavavea, E., Incerpi, S., Pedersen, J.z., Kourounakis, A. (2017). Balancing Antioxidant, Hypolipidemic and Anti-inflammatory Activity in a Single Agent: The Example of 2-Hydroxy-2-Substituted Morpholine, 1,4-Benzoxazine and 1,4-Benzothiazine Derivatives as a Potential Therapeutic Approach against Atherosclerosis. CURRENT MEDICINAL CHEMISTRY, 24(12), 1214-1227 [10.2174/0929867323666160814001803].

Balancing Antioxidant, Hypolipidemic and Anti-inflammatory Activity in a Single Agent: The Example of 2-Hydroxy-2-Substituted Morpholine, 1,4-Benzoxazine and 1,4-Benzothiazine Derivatives as a Potential Therapeutic Approach against Atherosclerosis

PEDERSEN, JENS ZACHO;
2017

Abstract

In line with our previous studies, we have developed through a rational design approach novel morpholine and benzoxa(or thia)zine lead compounds that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) interact and scavenge free radicals, b) inhibit the metal ion (Cu2+)-induced LDL oxidation c) act intracellularly as antioxidants in THP- 1 monocytes from a leukemic patient and d) inhibit the pro-inflammatory enzymes cycloxygenase-1 (COX-1) and -2 (COX-2) in vitro. Furthermore, two representative compounds were tested for their potential to decrease lipidemic parameters (TC, LDL and TG) in hyperlipidemic mice. Most derivatives indicated a remarkable antioxidant activity, while at the same time exhibited a significant in vitro anti-inflammatory activity, inhibiting COX-1 or/and COX-2 activity at 20 μΜ. Furthermore, after their long-term administration, compounds 6 and 8 afforded a considerable activity in a chronic experimental animal model of hyperlipidemia (after high fat diet administration). The multifunctional pharmacological profile exhibited by the compounds of this study renders them interesting lead compounds for the development of novel agents against atherosclerosis.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
Settore BIO/15 - Biologia Farmaceutica
Settore CHIM/08 - Chimica Farmaceutica
English
Con Impact Factor ISI
Design, synthesis, oxidative stress, lipid peroxidation, microsomes, LDL oxidation, squalene synthase inhibitors, cycloxygenase-1 and -2 inhibitors, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, atherosclerosis, high fat diet, multifunctional agents
Matralis, A., Bavavea, E., Incerpi, S., Pedersen, J.z., Kourounakis, A. (2017). Balancing Antioxidant, Hypolipidemic and Anti-inflammatory Activity in a Single Agent: The Example of 2-Hydroxy-2-Substituted Morpholine, 1,4-Benzoxazine and 1,4-Benzothiazine Derivatives as a Potential Therapeutic Approach against Atherosclerosis. CURRENT MEDICINAL CHEMISTRY, 24(12), 1214-1227 [10.2174/0929867323666160814001803].
Matralis, A; Bavavea, E; Incerpi, S; Pedersen, Jz; Kourounakis, A
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/170164
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