title: Synthesis and antiplatelet activity of antithrombotic thiourea compounds: biological and structure-activity relationship studies.
abstract: The incidence of hematological disorders has increased steadily in Western countries despite the advances in drug development. The high expression of the multi-resistance protein 4 in patients with transitory aspirin resistance, points to the importance of finding new molecules, including those that are not affected by these proteins. In this work, we describe the synthesis and biological evaluation of a series of N,N'-disubstituted thioureas derivatives using in vitro and in silico approaches. New designed compounds inhibit the arachidonic acid pathway in human platelets. The most active thioureas (compounds 3d, 3i, 3m and 3p) displayed IC50 values ranging from 29 to 84 µM with direct influence over in vitro PGE2 and TXA2 formation. In silico evaluation of these compounds suggests that direct blockage of the tyrosyl-radical at the COX-1 active site is achieved by strong hydrophobic contacts as well as electrostatic interactions. A low toxicity profile of this series was observed through hemolytic, genotoxic and mutagenic assays. The most active thioureas were able to reduce both PGE2 and TXB2 production in human platelets, suggesting a direct inhibition of COX-1. These results reinforce their promising profile as lead antiplatelet agents for further in vivo experimental investigations.
authors.affiliation: Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil. andrebiouff@gmail.com.
authors.forename: André Luiz
authors.initials: AL
authors.lastname: Lourenço
authors.affiliation: Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil. maxsaito@gmail.com.
authors.forename: Max Seidy
authors.initials: MS
authors.lastname: Saito
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. legdorneles@yahoo.com.br.
authors.forename: Luís Eduardo Gomes
authors.initials: LE
authors.lastname: Dorneles
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. gmviana@gmail.com.
authors.forename: Gil Mendes
authors.initials: GM
authors.lastname: Viana
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. pliniocs@yahoo.com.br.
authors.forename: Plínio Cunha
authors.initials: PC
authors.lastname: Sathler
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-909, RJ, Brazil. luciasequeira@yahoo.com.br.
authors.forename: Lúcia Cruz de Sequeira
authors.initials: LC
authors.lastname: Aguiar
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. marcelo@pharma.ufrj.br.
authors.forename: Marcelo
authors.initials: M
authors.lastname: de Pádula
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. thaisadomingos@yahoo.com.br.
authors.forename: Thaisa Francielle Souza
authors.initials: TF
authors.lastname: Domingos
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. agmfraga@yahoo.com.br.
authors.forename: Aline Guerra Manssour
authors.initials: AG
authors.lastname: Fraga
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. rangelfarmacia@gmail.com.
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. valeria@pharma.ufrj.br.
authors.forename: Valeria Pereira
authors.initials: VP
authors.lastname: de Sousa
authors.affiliation: LABiEMOL, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil. hcastrorangel@yahoo.com.br.
authors.forename: Helena Carla
authors.initials: HC
authors.lastname: Castro
authors.affiliation: LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil. lmcabral2@yahoo.com.br.
authors.forename: Lucio Mendes
authors.initials: LM
authors.lastname: Cabral
mesh_terms: D016718:Arachidonic Acid / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism
chemical_list: D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D013890:Thiourea; D015232:Dinoprostone