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.

Structure-activity relationship of three synthesized benzimidazole-based oligosaccharides in human platelet activation

“…A stable TxA 2 metabolite, thromboxane B 2 (TxB 2 ), is widely used as a prognostic risk marker of platelet activation in cardiovascular disease, which is closely related to cyclooxygenase (COX-1) and thromboxane synthetase (TXs) activity (34). A recent study found that a series of thioureas derivatives reduced TxB 2 production in human platelets via the direct inhibition of COX-1 for their antiplatelet effects (35). Currently, the basic structural requirements for the selective inhibition of TXs are a 1-imidazolyl or a 3-pyridyl moiety at one end of the molecule (36).…”

Non-invasive imaging and cellular tracking of pulmonary emboli by near-infrared fluorescence and positron-emission tomography

“…The haemolytic activity of the Cy7–PAR1–RIP variants was measured on healthy human erythrocytes and compared with the Cy7-wild-type TempL as reported previously 41 . Briefly, aliquots of human erythrocyte suspension in PBS (pH 7.4) were incubated with serial dilutions of the peptides (dissolved in DMSO before use) for 1 h at 37 °C.…”

1H and 13C NMR spectral assignments of 30 novel n‐methoxylated polyphenols containing thiourea skeletons

“…Thiourea‐derived compounds inhibit carbonic anhydrase II, epidermal growth factor receptor, the arachidonic acid pathway in human platelets, protein glycation, and nitric oxide synthases [1‐5] . They also show antimicrobial and anticancer activities .…”