@article{
author = "Stanković, Nevena and Mladenović, Milan and Matić, Sanja and Stanić, Snežana and Stanković, Vesna and Mihailović, Mirjana and Mihailović, Vladimir and Katanić, Jelena and Boroja, Tatjana and Vuković, Nenad and Sukdolak, Slobodan",
year = "2015",
abstract = "Two chroman-2,4-dione derivatives, namely 2a and 2f, were tested as in
vivo anticoagulants by seven days of continuous per os application to
adult male Wistar rats in a concentration of 20 mg/kg of body weight.
Derivatives were selected from a group of six previously
intraperitoneally applied compounds on the basis of presenting
remarkable activity in a concentration of 2 mg/kg of body weight. The
derivatives 2a and 2f are VKORC1 inhibitors, and comparison of the
absorption spectra, association, and dissociation constants suggested
that the compounds will be bound to serum albumin in the same manner as
warfarin is, leading to transfer towards the molecular target VKORC1.
After oral administration, the compounds proved to be anticoagulants
comparable with warfarin, inasmuch as the measured prothrombin times for
2a and 2f were 56.63 and 60.08 s, respectively. The INR values of 2a and
2f ranged from 2.6 to 2.8, recommending them as useful therapeutics in
the treatment of patients suffering from thromboembolic events and
atrial fibrillation. The high percentage of binding and high binding
affinity of 2a and 2f towards serum albumin reduced the risk of induced
internal bleeding. Several kinds of toxicity studies were performed to
investigate whether or not 2a and 2f can cause pathological changes in
the liver, kidneys, and DNA. The catalytic activity of serum enzymes,
concentration and catalytic activity of liver and kidney oxidative
stress markers and enzymes, respectively, as well as the observed
hepatic and renal morphological changes indicated that the compounds in
relation to warfarin induced irrelevant hepatic toxicity, no increment
of necrosis, and inconsiderable oxidative damage in the liver and
kidneys. Estimation of DNA damage using the comet assay confirmed that
2a and 2f caused no clinically significant genotoxicity. The higher
activity and lower toxicity of 2f recommended this compound as a better
drug candidate than 2a. (C) 2014 Elsevier Ireland Ltd. All rights
reserved.",
publisher = "Elsevier",
journal = "Chemico-Biological Interactions",
title = "Serum albumin binding analysis and toxicological screening of novel
chroman-2,4-diones as oral anticoagulants",
volume = "227",
doi = "10.1016/j.cbi.2014.12.005",
pages = "18-31"
}
