title: Synthesis and Preliminary Evaluation of N-Oxide Derivatives for the Prevention of Atherothrombotic Events.
abstract: Thrombosis is the main outcome of many cardiovascular diseases. Current treatments to prevent thrombotic events involve the long-term use of antiplatelet drugs. However, this therapy has several limitations, thereby justifying the development of new drugs. A series of N-oxide derivatives (furoxan and benzofuroxan) were synthesized and characterized as potential antiplatelet/antithrombotic compounds. All compounds (3a,b, 4a,b, 8a,b, 9a,b, 13a,b and 14a,b) inhibited platelet aggregation induced by adenosine-5-diphosphate, collagen, and arachidonic acid. All compounds protected mice from pulmonary thromboembolism induced by a mixture of collagen and epinephrine; however, benzofuroxan derivatives (13a,b and 14a,b) were the most active compounds, reducing thromboembolic events by up to 80%. N-oxide derivative 14a did not induce genotoxicity in vivo. In conclusion, 14a has emerged as a new antiplatelet/antithrombotic prototype useful for the prevention of atherothrombotic events.
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, SP, Brazil. leandroaugusto.rosseto@gmail.com.
authors.forename: Leandro Augusto
authors.initials: LA
authors.lastname: Rosseto
authors.affiliation: Departmento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, UNICAMP, Rua Tessália Vieira de Camargon.126, 13083-887, Campinas, SP, Brazil. mariaelisalopes@yahoo.com.br.
authors.forename: Maria Elisa Lopes
authors.initials: ME
authors.lastname: Pires
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, SP, Brazil. mimi.castanho@gmail.com.
authors.forename: Aylime Castanho Bolognesi
authors.initials: AC
authors.lastname: Melchior
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, SP, Brazil. bosquesi@fcfar.unesp.br.
authors.forename: Priscila Longhin
authors.initials: PL
authors.lastname: Bosquesi
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, SP, Brazil. alinerenatapavan2004@yahoo.com.br.
authors.forename: Aline Renata
authors.initials: AR
authors.lastname: Pavan
authors.affiliation: Departmento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, UNICAMP, Rua Tessália Vieira de Camargon.126, 13083-887, Campinas, SP, Brazil. sisi@fcm.unicamp.br.
authors.forename: Sisi
authors.initials: S
authors.lastname: Marcondes
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, SP, Brazil. chungmc@fcfar.unesp.br.
authors.forename: Man Chin
authors.initials: MC
authors.lastname: Chung
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, UNESP, Rodovia Araraquara Jaú Km 01, 14801-902, Araraquara, SP, Brazil. santosjl@fcfar.unesp.br.
authors.forename: Jean Leandro Dos
authors.initials: JL
authors.lastname: Santos
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003094:Collagen / Q000009:adverse effects; D004195:Disease Models, Animal; D004837:Epinephrine / Q000009:adverse effects; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000139:chemically induced / Q000517:prevention & control*
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D001583:Benzoxazoles; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; C014354:benzofuroxan; D003094:Collagen; D004837:Epinephrine
keywords: N-oxide; antiplatelet activity; atherothrombosis; benzofuroxan; bleeding time; furoxan; genotoxicity