Synthesis of novel 3-carboxamide-benzocoumarin derivatives as orally active antithrombotic agents

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 23, 2011, Pages 7034-7040

  Sashidhara, Koneni V ^a   Kumar, Abdhesh ^a   Kumar, Manoj ^a   Singh, S ^a   Jain, Manish ^a   Dikshit, Madhu ^a  

^a CENTRAL DRUG RESEARCH INSTITUTE   (India)

Author keywords

3 Carboxamide benzocoumarins; Antithrombotic activity; Aspirin; Bleeding time; Synthesis; Warfarin

Indexed keywords

3 CARBOXAMIDE BENZOCOUMARIN DERIVATIVE; ACETYLSALICYLIC ACID; ANTICOAGULANT AGENT; COUMARIN DERIVATIVE; UNCLASSIFIED DRUG; WARFARIN;

ARTICLE; BLEEDING TIME; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; PROTHROMBIN TIME; STRUCTURE ANALYSIS;

ADMINISTRATION, ORAL; ANIMALS; ASPIRIN; BLOOD COAGULATION; COUMARINS; FIBRINOLYTIC AGENTS; MICE; MOLECULAR STRUCTURE; WARFARIN;

EID: 80255138713     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.09.100     Document Type: Article

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16. Mouse thrombosis model: Pulmonary thromboembolism was induced by a method as described by DiMinno and Silver (1983). The compounds to be tested (30 μmol/kg), standard drugs or the vehicle were administered by oral route 60 min prior to the thrombotic challenge. Ten mice were used for evaluating the effect of each test compound, while a group of five mice was used to evaluate the effect of standard drugs or vehicle. A mixture of collagen (1.5 mg/kg) and adrenaline (0.5 mg/kg) was injected into the tail vein to induce hind limb paralysis or death. Results have been reported as% protection, which represents the protection against hind limb paralysis or death. The test compounds exhibiting protection equivalent to standard drugs (30 μmol/kg) were considered as active molecules (DiMinno, G.; Silver, M. J. J. Pharmacol. Exp. Ther. 1983, 225, 57).
17. Bleeding time: Bleeding time in mice was evaluated by the method of Dejana et al. (1979) to assess the increase in bleeding time in comparison to aspirin at its optimal antithrombotic dose. The tail 2 mm from tip of mice was incised and the blood oozed was soaked on a filter paper, which was monitored at an interval of 10-15 s till the bleeding stopped. The time elapsed from the tail tip incision to the stoppage of bleeding was recorded as the bleeding time. The tested compounds (30 μmol/kg), standard drugs (30 μmol/kg) or vehicle was given orally 60 min prior to the tail incision in a group of five mice each (Dejana, E.; Callioni, A.; Quintana, A. Giovanni G. Thromb. Res. 1979, 15, 191).
18. Coagulation parameters: Animals were anaesthetized under anesthetic ether and blood was drawn from the heart into a plastic syringe containing 2.5% tri-sodium citrate. The blood was centrifuged at 2500g for 20 min 20 °C to plasma. Prothrombin time (PT), were assayed in plasma samples of all the groups within 2 h of sample collection. Assay was performed using commercial kits as per manufacturer's instructions and measured by using a Coagulometer (Start4 Semi automated, Young Instruments, Stago, France. Essler, M.; Retzer, M.; Bauer, M.; Zangl, K. J.; Tigyi, G.; Siess, W. Ann. N.Y. Acad. Sci. 2000, 905, 282).