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.
Highlights
According to the World Health Organization, cardiovascular disease will be a leading cause of death in developed and developing countries by 2015
In order to develop thioureas having an unlikely propensity to act as substrates for MRPs, the carboxylate function was rejected for the final products and replaced by hydrophobic or H-bond acceptor (HBA) groups unable to produce organic anions at physiological pH
Co-substitutions of a potential lead molecule tailoring a HBA and a hydrophobic group was recently reported as an expressive approach for selective inhibition of cyclooxygenases, since it increases the molecular similarities to arachidonic acid by mimicking its 20-carbon hydrophobic ω-chain and the carboxylate group, which acts as a strong HBA group [25,27]
Summary
According to the World Health Organization, cardiovascular disease will be a leading cause of death in developed and developing countries by 2015. Cardiovascular and thromboembolic events are already the major causes of death in Western countries [1]. The inappropriate activation of the hemostatic system contributes to the development of severe pathophysiological disorders, including the thromboembolic diseases, such as atherothrombosis and venous thromboembolism [4,5]. Antithrombotic drugs, including antiplatelet agents (e.g., clopidogrel, aspirin, tirofiban), are the primary treatment option for these diseases. They can lead to serious adverse reactions in some patients, including bleeding, neutropenia, thrombocytopenia and drug resistance [1,6,7,8,9,10]
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