Abstract
In line with our previous studies, novel morpholine and benzoxa(or thia)zine lead compounds have been developed through a rational design that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) intercept 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 cyclooxygenase-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. In addition, after their long-term administration, compounds 6 and 8 afforded 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.
Keywords: Design, synthesis, oxidative stress, lipid peroxidation, microsomes, LDL oxidation, squalene synthase inhibitors, cyclooxygenase-1 and -2 inhibitors, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, atherosclerosis, high fat diet, multifunctional agents.
Current Medicinal Chemistry
Title: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 Rational Therapeutic Approach against Atherosclerosis
Volume: 24 Issue: 12
Author(s): Alexios N. Matralis, Eugenia-Ismini Bavavea, Sandra Incerpi, Jens Z. Pedersen and Angeliki P. Kourounakis*
Affiliation:
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, 15771 Athens,Greece
Keywords: Design, synthesis, oxidative stress, lipid peroxidation, microsomes, LDL oxidation, squalene synthase inhibitors, cyclooxygenase-1 and -2 inhibitors, triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, atherosclerosis, high fat diet, multifunctional agents.
Abstract: In line with our previous studies, novel morpholine and benzoxa(or thia)zine lead compounds have been developed through a rational design that modulate a multiplicity of targets against atherosclerosis. We have evaluated the most promising compounds for their efficiency to a) intercept 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 cyclooxygenase-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. In addition, after their long-term administration, compounds 6 and 8 afforded 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.
Export Options
About this article
Cite this article as:
Matralis N. Alexios, Bavavea Eugenia-Ismini, Incerpi Sandra, Pedersen Z. Jens and Kourounakis P. Angeliki*, 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 Rational Therapeutic Approach against Atherosclerosis, Current Medicinal Chemistry 2017; 24 (12) . https://dx.doi.org/10.2174/0929867323666160814001803
DOI https://dx.doi.org/10.2174/0929867323666160814001803 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
24-Hour Blood Pressure Control – A Predictor for Clinical Outcomes
Current Hypertension Reviews Endothelial Cell Regulation of Cardiac Metabolism Following Diabetes
Cardiovascular & Hematological Disorders-Drug Targets Preface
Current Topics in Medicinal Chemistry Anticoagulant Therapy During Pregnancy for Maternal and Fetal Acquired and Inherited Thrombophilia
Current Medicinal Chemistry Pregnancy in Type 2 Diabetes Mellitus - Problems & Promises
Current Diabetes Reviews Polyunsaturated Fatty Acids in Pathological Retinal Angiogenesis
Current Nutrition & Food Science A Role for Endothelin-1 in Peripheral Vascular Disease
Current Vascular Pharmacology The Role of Adipocytokines in Atherogenesis and Atheroprogression
Current Drug Targets Periodontal Bacteria Aggravate Chronic Renal Failure Induced by Subtotal Nephrectomy in Mice
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Impact of Macrophages in Atherosclerosis
Current Medicinal Chemistry Genetic Variations of the Hemostatic System as Risk Factors for Venous and Arterial Thrombotic Disease
Current Genomics Impact of MCP -1 in Atherosclerosis
Current Pharmaceutical Design Walnut Extract Inhibits the Fibrillization of Amyloid Beta-Protein, and also Defibrillizes its Preformed Fibrils
Current Alzheimer Research Biology and Clinical Relevance of Mannose-Binding Lectin
Drug Design Reviews - Online (Discontinued) Anesthetic Cardioprotection in Relation to Mitochondria: Basic Science
Current Pharmaceutical Design Genistein as a Potential Anticancer Agent Against Head and Neck Squamous Cell Carcinoma
Current Topics in Medicinal Chemistry A Comprehensive Review on Recent Developments in the Field of Biological Applications of Potent Pyrazolines Derived from Chalcone Precursors
Letters in Drug Design & Discovery Cardiovascular Disease and Dyslipidemia: Beyond LDL
Current Pharmaceutical Design Chronopharmaceutical Delivery of Anti-Inflammatory Drugs
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Macrophage Differentiation to Foam Cells
Current Pharmaceutical Design