Biochemical and pharmacological evaluation of 4-hydroxychromen-2-ones bearing polar C-3 substituents as anticoagulants
2012
Autori:
Mladenović, MilanMihailović, Mirjana
Bogojević, Desanka
Vuković, Nenad
Sukdolak, Slobodan
Matić, Sanja
Nićiforović, Neda
Mihailović, Vladimir
Mašković, Pavle
Vrvić, Miroslav M.
Solujić, Slavica
Tip dokumenta:
Članak u časopisu (Objavljena verzija)
,
© 2012 Elsevier Masson SAS.
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
The objective of this study was to investigate in vitro and in vivo anticoagulant activity of sixteen 4-hydroxycoumarin derivatives bearing polar C-3 scaffolds. The activity was evaluated by measuring prothrombin time. Enhanced anticoagulant activity in vitro was observed for all tested compounds. Upon successive administration of 0.5 mg/kg of body weight to adult Wistar rats, over a period of five days, four derivatives (2b, 4c, 5c and 9c) presented anticoagulant activity in vivo. The most active compound was 2b, with PT = 30.0 s. Low or non-toxic effects in vivo were determined based on the catalytic activity of liver enzymes and the concentration of bilirubin, iron and proteins. Metabolic pathways of the most active compounds in vivo were determined after GC/MS analysis of collected rat urine samples. The excretion occurs by glucuronidation of 7-hydroxy forms of tested derivatives. In vivo results were described using PLS-based CoMFA and CoMSIA 3D-QSAR studies, which showed CoMFA-SE (q2 = 0.738) and CoMSIA-SEA (q2 = 0.763) to be the statistically most relevant models. Furthermore, molecular docking and DFT mechanistic studies performed on the rat VKORC1 homology model revealed interactions between the 4-OH coumarin group in the form of phenolic anion and the Cys135 catalytic site in the transition state.
Ključne reči:
4-Hydroxycoumarins; In vivo anticoagulant activity; Metabolic pathways; Homology modeling; Mechanistic studies; 3D-QSARIzvor:
European Journal of Medicinal Chemistry, 2012, 54, 144-158Finansiranje / projekti:
- Signalni molekuli u dijabetesu: identifikacija potencijalnih bioloških markera uključenih u modifikaciju i integraciju signalnih puteva u cilju predikcije i intervencije u dijabetesu (RS-MESTD-Basic Research (BR or ON)-173020)
- Simultana bioremedijacija i soilifikacija degradiranih prostora, za očuvanje prirodnih resursa biološki aktivnih supstanci i razvoj i proizvodnju biomaterijala i dijetetskih proizvoda (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-43004)
- Preklinička ispitivanja bioaktivnih supstanci (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41010)
DOI: 10.1016/J.EJMECH.2012.04.036
ISSN: 0223-5234
PubMed: 22633008