title: Studies on the antiplatelet and antithrombotic profile of anti-inflammatory coumarin derivatives.
abstract: The interest towards coumarin-based structures stems from their polypharmacological profile. Herein, we present a series of Mannich bases and 7-azomethine-linked coumarin derivatives exhibiting antiplatelet and antithrombotic activities, in addition to the already known anti-inflammatory and antioxidant activities. Among others, compounds 15 and 16 were found to be the most potent and selective inhibitors of platelet aggregation whereas compound 3 also proved to be the most potent in the clot retraction assay. Structure-activity relationship studies were conducted to elucidate the molecular determinants responsible for the herein observed activities. The chance of inhibiting cyclooxygenase-1 was also investigated for evaluating the platelet aggregation induced by arachidonic acid. Taken together, these results suggest that the investigation of other targets connected to the antiplatelet activity, such as phosphodiesterase-3 (PDE3), could be a viable strategy to shed light on the polypharmacological profile of coumarin-based compounds. Docking simulations towards PDE3 were also carried out.
authors: a Laboratory of Hygiene and Environmental Protection , Democritus University of Thrace , Alexandroupolis , Greece .
authors: Christos
authors: C
authors: Kontogiorgis
authors: b Dipartimento di Farmacia - Scienze del Farmaco , Universita degli Studi Bari "Aldo Moro" , Bari , Italy .
authors: Orazio
authors: O
authors: Nicolotti
authors: b Dipartimento di Farmacia - Scienze del Farmaco , Universita degli Studi Bari "Aldo Moro" , Bari , Italy .
authors: Giuseppe Felice
authors: GF
authors: Mangiatordi
authors: c Department of Pharmacy , University of Parma , Parma , Italy .
authors: Massimiliano
authors: M
authors: Tognolini
authors: d Department of Pharmaceutical Chemistry , School of Pharmacy, Aristotle University of Thessaloniki , Thessaloniki , Greece , and.
authors: Foteini
authors: F
authors: Karalaki
authors: c Department of Pharmacy , University of Parma , Parma , Italy .
authors: Carmine
authors: C
authors: Giorgio
authors: e Department of Chemistry and Drug Technologies , "Sapienza" University of Rome , Rome , Italy.
authors: Alexandros
authors: A
authors: Patsilinakos
authors: b Dipartimento di Farmacia - Scienze del Farmaco , Universita degli Studi Bari "Aldo Moro" , Bari , Italy .
authors: Angelo
authors: A
authors: Carotti
authors: d Department of Pharmaceutical Chemistry , School of Pharmacy, Aristotle University of Thessaloniki , Thessaloniki , Greece , and.
authors: Dimitra
authors: D
authors: Hadjipavlou-Litina
authors: c Department of Pharmacy , University of Parma , Parma , Italy .
authors: Elisabetta
authors: E
authors: Barocelli
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003374:Coumarins; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; C030123:coumarin; D051545:Cyclooxygenase 1; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517287:PDE3A protein, human
keywords: Antiplatelet; PDE3 inhibitors; QSAR; antithrombotic; coumarin derivatives; docking studies