Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies

Molecules

André Luiz Lourenço²  Max Seidy Saito²  Luís Eduardo Gomes Dorneles³  Gil Mendes Viana³  Plínio Cunha Sathler³  Lྫྷia Cruz de Sequeira Aguiar¹  Marcelo de Pฝula³  Thaisa Francielle Souza Domingos³  Aline GuerraManssour Fraga³  Carlos Rangel Rodrigues⁴  Valeria Pereira de Sousa³  Helena Carla Castro⁵  Lucio Mendes Cabral³ 

[1] Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-909, RJ, Brazil; E-Mail:;Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil; E-Mails:;LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil; E-Mails:;ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil; E-Mail:;LABiEMOL, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil

关键词: thioureas;    antiplatelet properties;    in silico evaluation;   

DOI  :  10.3390/molecules20047174

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.