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
Authors:
Stanković, NevenaMladenović, Milan
Mihailović, Mirjana
Arambašić Jovanović, Jelena
Uskoković, Aleksandra
Stanković, Vesna
Mihailović, Vladimir
Katanić, Jelena
Matić, Sanja
Solujić, Slavica
Vuković, Nenad
Sukdolak, Slobodan
Document Type:
Article (Published version)
,
© 2014 Elsevier B.V.
Metadata
Show full item recordAbstract:
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.
Keywords:
3-D pharmacophore; Chroman-2,4-diones; Anticoagulant activity in vivo; Histopathology; Molecular dockingSource:
European Journal of Pharmaceutical Sciences, 2014, 55, 1, 20-35Funding / projects:
- Signaling molecules in diabetes: search for potential targets in intrinsic pathways for prediction and intervention in diabetes (RS-MESTD-Basic Research (BR or ON)-173020)
- Simultaneous Bioremediation and Soilification of Degraded Areas to Preserve Natural Resources of Biologically Active Substances, and Development and Production of Biomaterials and Dietetic Products (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-43004)
- Modulation of antioxidative metabolism in plants for improvement of plant abiotic stress tolerance and identification of new biomarkers for application in remediation and monitoring of degraded biotopes (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-43010)
DOI: 10.1016/j.ejps.2014.01.004
ISSN: 0928-0987
PubMed: 24468630