新型氟化达比加群衍生物的分子设计、合成及抗凝血活性研究

发布时间：2018-01-20 15:40

  本文关键词： 分子设计 合成 抗凝活性 氟化 达比加群衍生物　出处：《上海应用技术大学》2016年硕士论文　论文类型：学位论文

【摘要】：本文研究主要内容是结合达比加群在抗凝血治疗中的优势以及氟原子在药物分子设计中的优点,利用计算机辅助药物设计软件SYBYL-X 2.0. (Tripos Inc., St. Louis, USA)下的Surflex-Dock模块,以凝血酶蛋白(PDB:1KTS)作为受体对达比加群的衍生物进行计算机辅助模拟和分子对接,在直接凝血酶抑制剂达比加群中引入氟,并且对其进行结构修饰,设计出一系列新颖的氟化达比加群衍生物,通过对这些化合物进行计算机模拟打分,筛选出打分值高的15个化合物,通过迈克尔加成、酰化、还原、缩合闭环、Pinner反应、以及水解反应最终合成新型氟化达比加群衍生物。通过对这些化合物进行抑制率筛选,11个衍生物被选出进行体外抗凝血活性测试研究,测试结果表明,所有化合物具有稳定温和的抗凝血活性,其中化合物15f、15k、15n和150与阳性对照物达比加群(IC50= 1.23 nmol/L)相比较,具有相当的抗凝血活性,其IC50值分别为1.81、3.21、3.69和2.16nmol/L。选取化合物15k以及150进一步对其进行体内生物活性测试--对SD大鼠动静脉血栓形成的影响,在所检测的2种受试物中,均可有效抑制动静脉血栓的栓子重量,且作用均与阳性对照物达比加群相当,抑制率分别为(76.23±3.68)%和(84.66±0.56)%,能够作为抗凝血药物候选药物对其进行更深层次的研究。
[Abstract]:The main content of this study is to combine the advantages of Darbica in anticoagulant therapy and the advantages of fluorine atom in drug molecular design. The computer aided drug design software (SYBYL-X 2.0. Tripos Inc.St. Louis) was used. The Surflex-Dock module with thrombin protein PDB: 1KTS as the receptor was used for the computer aided simulation and molecular docking of the derivatives of the Darbita group. Fluorine was introduced into the direct thrombin inhibitor Darby adders and modified with structure. A series of novel derivatives were designed and scored by computer simulation. A total of 15 compounds with high scoring value were selected, which were synthesized by Michael addition, acylation, reduction, condensation and closed loop Pinner reaction. Through screening the inhibition rate of these compounds, 11 derivatives were selected for in vitro anticoagulant activity test, the results showed that. All the compounds have stable and mild anticoagulant activity, of which compound 15fN 15k. The IC50 values of 15n and 150 were 1.81nmol / L and 1.81nmol / L, respectively, compared with those of the positive control group (IC 50 = 1.23 nmol / L). 3.69 and 2.16 nmol / L. selected compounds 15k and 150 to further test their bioactivity in vivo-the effect on arteriovenous thrombosis in SD rats. In the two tested samples, the embolus weight of arteriovenous thrombus was inhibited effectively, and the effect was similar to that of the positive control group. The inhibition rates were 76.23 卤3.68% and 84.66 卤0.56%, respectively, which could be further studied as anticoagulant drug candidates.
【学位授予单位】：上海应用技术大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R91;R914.5;R96
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本文编号：1448744