Synthesis and toxicological studies of in vivo anticoagulant activity of novel 3-(1-aminoethylidene)chroman-2,4-diones and 4-hydroxy-3-(1-iminoethyl)-2H-chromen-2-ones combined with a structure-based 3-D pharmacophore model.
2014
Autori:
Stanković, NevenaMladenović, Milan
Mihailović, Mirjana
Arambašić Jovanović, Jelena
Uskoković, Aleksandra
Stanković, Vesna
Mihailović, Vladimir
Katanić, Jelena
Matić, Sanja
Solujić, Slavica
Vuković, Nenad
Sukdolak, Slobodan
Tip dokumenta:
Članak u časopisu (Objavljena verzija)
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© 2014 Elsevier B.V.
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Eight synthesized 3-(1-aminoethylidene)chroman-2,4-diones and 4-hydroxy-3-(1-iminoethyl)-2H-chromen-2-ones were evaluated as in vivo anticoagulants by intraperitoneal application to adult male Wistar rats in order to examine their pharmacological potential, evaluate ther toxicity and propose the mechanism of action. Two of them, 2f and 2a, in concentration of 2mg/kg of body weight, presented remarkable activity (PT=130s; PT=90s) upon seven days of continuous application. The results of rat serum and liver biochemical screening, as well those of histopathological studies, proved the compounds to be non-toxic. Activity of the compounds was further examined on the molecular level. Here, molecular docking studies were performed to position the compounds in relation to the active site of VKORC1 and determine the bioactive conformations. Docking results suggested a non-covalent mode of action during which the proton transfer occurs from Cys135 SH towards 4-carbonyl group of anticoagulant. All crucial interactions for anticoagulant activity were confirmed in generated structure-based 3-D pharmacophore model, consisted of hydrogen bond acceptor and hydrophobic aromatic features, and quantified by a best correlation coefficient of 0.97.
Ključne reči:
3-D pharmacophore; Chroman-2,4-diones; Anticoagulant activity in vivo; Histopathology; Molecular dockingIzvor:
European Journal of Pharmaceutical Sciences, 2014, 55, 1, 20-35Finansiranje / projekti:
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DOI: 10.1016/j.ejps.2014.01.004
ISSN: 0928-0987
PubMed: 24468630