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Title: 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
Authors: Stankovic, Nevena
Mladenović M.
Mihailovic, Mirjana
Arambašić Jovanović, Jelena
Uskoković, Aleksandra
Stankovic, Vesna
Mihailovic, Vladimir
Katanić Stanković, Jelena S.
Matić, Sanja
Solujic A.
Vukovic, Nenad
Sukdolak S.
Journal: European Journal of Pharmaceutical Sciences
Issue Date: 13-May-2014
Abstract: 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 2 mg/kg of body weight, presented remarkable activity (PT = 130 s; PT = 90 s) 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. © 2014 Elsevier B.V. All rights reserved.
Type: Article
DOI: 10.1016/j.ejps.2014.01.004
ISSN: 09280987
SCOPUS: 84893924133
Appears in Collections:Faculty of Medical Sciences, Kragujevac
Faculty of Science, Kragujevac
Institute for Information Technologies, Kragujevac
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