| Autor: |
Tsiailanis AD; Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece., Vrettos EI; Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece., Choleva M; School of Health Science and Education, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece., Kiriakidi S; Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece., Ganai AM; Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville), Durban, South Africa., Patha TK; Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville), Durban, South Africa., Karpoormath R; Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville), Durban, South Africa., Mavromoustakos T; Department of Chemistry, National and Kapodistrian University of Athens, Athens, Greece., Fragopoulou E; School of Health Science and Education, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece., Tzakos AG; Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece.; Institute of Materials Science and Computing, University Research Center of Ioannina (URCI), Ioannina, Greece. |
| Abstrakt: |
Despite the scientific progression in the prevention and treatment of cardiovascular diseases (CVDs) they remain the leading cause of mortality and disability worldwide. The classic treatment involves the simultaneous dosing of two antiplatelet drugs, aspirin and clopidogrel/prasugrel. However, besides drug resistance, severe side effects have been also manifested including acute bleeding and toxicity. Thus, new therapeutic agents with enhanced efficacy and diminished side effects are of importance. Towards this end, omega-3 (ω-3) fatty acids have demonstrated potent efficacy against CVDs through inhibiting platelet aggregation that bears a pivotal role in atherothrombosis. Another factor that displays a critical role in the pathogenesis of cardiovascular diseases is the renin-angiotensin system (RAS), and especially the AT 1 R blocker losartan that has been reported to exert antiplatelet activity mediated by this receptor. Along these lines, we envisaged developing a molecular hybrid consisted of docosahexaenoic acid (ω-3 fatty acid) and losartan, that could exert a notable antiplatelet effect against CVDs. The design and synthesis of the new DHA-losartan hybrid, designated DHA-L, bestowed with the additive properties of the parent compounds, is reported. In silico studies were first exploited to validate the potential of DHA-L to retain losartan's ability to bind AT 1 R. The antiplatelet activity of DHA-L was evaluated against in vitro platelet aggregation induced by several platelet agonists. Notably, the hybrid illustrated a pleiotropic antiplatelet profile inhibiting platelet aggregation through multiple platelet activation pathways including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1) and collagen receptors. The stability of DHA-L in human plasma and in a wide range of pH values was also evaluated over time using an HPLC protocol. The hybridization approach described herein could pave the way for the development of novel potent multitargeted therapeutics with enhanced antiplatelet profile.Communicated by Ramaswamy H. Sarma. |
