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Molecules 2015, 20(4), 7174-7200; doi:10.3390/molecules20047174

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

1
Programa de Pós-graduação em Patologia, Departamento de Patologia, Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil
2
LabTIF, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil
3
Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-909, RJ, Brazil
4
ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro CEP 21941-902, RJ, Brazil
5
LABiEMOL, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense (UFF), Niterói CEP 24033-900, RJ, Brazil
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 27 February 2015 / Revised: 8 April 2015 / Accepted: 13 April 2015 / Published: 20 April 2015
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [3703 KB, uploaded 20 April 2015]   |  

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. View Full-Text
Keywords: thioureas; antiplatelet properties; in silico evaluation thioureas; antiplatelet properties; in silico evaluation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lourenço, A.L.; Saito, M.S.; Dorneles, L.E.G.; Viana, G.M.; Sathler, P.C.; Aguiar, L.C.S.; de Pádula, M.; Domingos, T.F.S.; Fraga, A.G.M.; Rodrigues, C.R.; de Sousa, V.P.; Castro, H.C.; Cabral, L.M. Synthesis and Antiplatelet Activity of Antithrombotic Thiourea Compounds: Biological and Structure-Activity Relationship Studies. Molecules 2015, 20, 7174-7200.

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