Human thromboxane synthase: comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel

Sathler, P.C; Santana, Marcos Vinicius da Silva; Lourenço, André Luiz; Rodrigues, Carlos Rangel; Abreu, Paula Alvarez; Cabral, Lúcio Mendes; Castro, Helena C.

doi:10.3109/14756366.2013.817403

Cited by 16 publications

(9 citation statements)

References 26 publications

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“…In physiological conditions, the release of arachidonic acid (AA) from the platelet membranes generates thromboxane A 2 (TXA 2 ), a potent platelet agonist, leading to shape-change, granule release and platelet aggregation [ 28 , 29 ]. The main enzymes responsible for the production of TXA 2 in platelets are COX-1 and thromboxane synthase (TXS), both whose inhibition is known to prevent platelet aggregation [ 30 , 31 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2015

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Chang¹,

Hsu

Yang

et al. 2017

International Journal of Molecular Medicine

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Antiplatelet agents have considerable benefits in the treatment of thromboembolic diseases; however, these agents still have substantial limitations due to their severe side-effects. In this study, the antiplatelet activity of three newly synthesized saccharide based benzimidazole derivatives, M3BIM, Malto-BIM and Melibio-BIM, in collagen and thrombin-stimulated human platelets in vitro was examined. Among the compounds tested, only compound M3BIM exerted concentration (20-60 µM)-dependent inhibitory effects against collagen (1 µg/ml) and thrombin (0.01 U/ml)-induced washed human platelet aggregation. Moreover, at a concentration of 60 µM, M3BIM distinctly abolished collagen-induced adenosine triphosphate (ATP) release and intracellular Ca2+ mobilization. Additionally, this compound attenuated the collagen-induced phosphorylation of p47, a marker of the activation of protein kinase C (PKC) and p38 mitogen-activated protein kinase (MAPK). However, Malto-BIM and Melibio-BIM were not effective in this regard. Moreover, the toxic effects of these compounds were evaluated using zebrafish embryo toxicity (ZET) assay, and the results revealed that all three compounds had no comparative cytotoxicity within the range of 25-200 µM. Overall, the results of this study provide evidence for the inhibitory effects of M3BIM on collagen-induced platelet aggregation in vitro compared to other imidazole derivatives. The presence of 1-imidazolyl moiety at one end with a longer chain length (three sugar moieties) may be mainly responsible for the observed effects of M3BIM. These results suggest that compound M3BIM may be used as a potential candidate for the treatment of aberrant platelet activation-related diseases as it inhibits the activation of p47 and p38 MAPK, and reduces ATP release and Ca2+ mobilization.

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“…Several studies indicate that cardiovascular disorders are some important factors health worldwid [1][2][3]. There are several drugs for the treatment of some of these clinical pathologies such as acetylsalicylic acid (ciclooxygenase inhibitor) [4], dazoxiben (thromboxane synthase inhibitor) [5], ridogrel (a dual thromboxane synthase blocker and receptor antagonist) [6], daltroban [7] and ramatroban (thromboxane A2 receptor antagonists) [8]. However, some these drugs can produce several secondary effects such as gastrointestinal erosions, hemorrhage and renal injury [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and theoretical analysis of interaction from an adamantane-steroid derivative with both COX-1 and COX-2

2019

Biointerface Res Appl Chem

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Several inhibitors of cyclooxygenases (COX-1 and COX-2) have been prepared using different protocols; however, these methods use some reagents that require special conditions. The objective of this study was synthesize a new adamantane-steroid derivative to evaluate their theoretical activity against both COX-1 and COX-2 enzymes using either indomethacin and rofecoxib as controls in a docking method. Theorethical data showed that the adamantane-steroid derivative could have a higher affinity for COX-1; this interaction could produce changes on biological activity of COX-1 enzyme. In onclusion, the theoretical evaluation indicates that this steroid-derivative could be a good prospect as an inhibitor of COX-1.

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Human thromboxane synthase: comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel

Cited by 16 publications

References 26 publications

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

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

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

Synthesis and theoretical analysis of interaction from an adamantane-steroid derivative with both COX-1 and COX-2

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