A new class of anti-thrombosis hexahydropyrazino-[1′,2′:1,6]pyrido-[3,4-b]-indole-1,4-dions: Design, synthesis, logK determination, and QSAR analysis
| Autor: | Wei-Xuan Wang, Chao Wang, Guofeng Wu, Shiqi Peng, Jiawang Liu, Guohui Cui, Ming Zhao, Ziding Zhang |
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| Rok vydání: | 2007 |
| Předmět: |
Indoles
Time Factors Platelet Aggregation Pyridones Swine Stereochemistry Clinical Biochemistry Lysine Administration Oral Quantitative Structure-Activity Relationship Pharmaceutical Science Biochemistry Chemical synthesis chemistry.chemical_compound Acetic acid Fibrinolytic Agents Drug Discovery Animals Molecular Biology Racemization chemistry.chemical_classification Indole test Dose-Response Relationship Drug Molecular Structure Organic Chemistry Free base Rats Amino acid chemistry Drug Design Injections Intravenous Lactam Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 15:5672-5693 |
| ISSN: | 0968-0896 |
| Popis: | Based on the fact that the cyclization of N -[(3 S )]-1,2,3,4-tetrahydro-β-carboline-3-carboxyl]- l -lysine in both of acetic acid aqueous (5%) and rat plasma gave the same product and the hypothesis that the cyclization product is antithrombotic active, we report the synthesis, in vitro anti-aggregation, and in vivo anti-thrombosis activity of 20 hexahydropyrazino[1′,2′:1,6]pyrido[3,4- b ]indole-1,4-dions ( 5a – t ) as potential anti-thrombosis agents in this study. Two intermediates (tetrahydro-β-carboline-3-carboxy- l -amino acid benzylesters, 2-aminoacyltetrahydro-β-carboline-3-carboxylic acid benzylesters) were prepared and used for the cyclization to form 5a – t . Coupling hydrochloric acid salt of tetrahydro-β-carboline-3-carboxylic acid esters and Boc-amino acids in the reported literature usually generates very low yield products accompanied by racemization. However, in our case, the free base of tetrahydro-β-carboline-3-carboxylic acid benzylester produced the desired products in high yields and without racemization. The anti-thrombosis results from both in vitro and in vivo studies revealed that 5a – t may be a new class of anti-thrombosis agents with potent effective concentration at 0.5 μmol/kg with oral administration. Moreover, a QSAR analysis was performed on these 20 compounds by using molecular descriptors generated by e-dragon server. Although the activities of these compounds are weakly correlated with the log P values, the current QSAR analysis revealed that the anti-thrombotic activity of these compounds can be explained by their steric and electrostatic effects. |
| Databáze: | OpenAIRE |
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