甲氟喹衍生物的设计、合成及抗血吸虫活性研究以及泛酸合成酶抑制剂的设计、合成及活性研究
发布时间：2018-12-06 13:29
【摘要】：本文包含两个部分。本文第一部分是甲氟喹衍生物的设计、合成及抗血吸虫活性研究血吸虫病是由血吸虫引起的一种急性与慢性寄生虫病。寄生人体的主要虫种有日本血吸虫、曼氏血吸虫和埃氏血吸虫。目前吡喹酮(PZQ)是用于治疗日本血吸虫病的唯一特效药物。过分依赖吡喹酮必然存在潜在的危险。抗疟药甲氟喹被发现对血吸虫童虫和成虫均有很高的杀灭作用,但临床研究发现其单独使用时对血吸虫病治疗效果不佳。本文将甲氟喹作为先导物,为了减小甲氟喹的中枢神经副作用,参考β受体抑制剂的设计原理,构建了新的结构骨架,在甲氟喹的侧链中插入一个氧亚甲基,通过变换不同的氨基和芳环来进行构效关系研究。全文共合成了52个新化合物,24个化合物体外对日本血吸虫童虫的LD50小于10μM,其中有10个化合物抗童虫活性与甲氟喹相当或者更好。7个化合物体外对日本血吸虫成虫的LD50小于10μM。其中化合物QC010105与甲氟喹体外抗血吸虫童虫和成虫活性相当。虽然该类化合物在体内实验中表现不佳,但证明了该类化合物是一类值得进一步研究的抗血吸虫化合物。下一步研究可以针对二三氟甲基喹啉这个基团进行改造,期待获得活性更好的抗血吸虫新药。本文第二部分是泛酸合成酶抑制剂的设计、合成和活性研究。耐药结核病例的不断增长,和艾滋病的流行,使得研发抗结核药物是新药研发的热点之一,虽然近3年有两个抗耐药结核的药物被批准上市,但治疗耐药结核的形式却依然严峻,不断有新的耐药菌被发现,并且XDR-TB目前依然无药可治。由pan C基因编码的泛酸合成酶是一个可能的抗结核药物作用靶点,它与目前广泛运用的一线抗结核药物的作用靶点完全不同,从而不会导致交叉耐药。目前发现的泛酸合成酶抑制剂的数量很有限,而且所有抑制剂几乎都对结核杆菌无效。本文以模拟泛酸合成酶催化反应的中间体的方式合成了10个新的泛酸合成酶抑制剂。所有抑制剂都在C2位保持了与泛酸合成酶催化的反应中间体相同的手性构象,并分别对Pantioc acid部分,糖环部分以及碱基部分进行改造获得了不同的抑制剂。我们将抑制剂4-8进行了抑酶活性的测定,得到其抑制常数,并利用计算机辅助设计对其结果进行了解释。最后对其进行了抗结核杆菌的活性评价。所有抑制剂是都是底物pantoate的竞争性抑制剂,活性最好的抑制剂4相对于pantoate的Ki为0.27±0.04μM,与文献报道的差向异构体混合物3j相当(Ki为0.3μM)。虽然测定Ki的方法不同,但也说明pantioc acid片段的C2位的手性对活性影响不大。通过计算机模拟对接试验,我们发现抑制剂4与蛋白质共有9处氢键相互作用,作用很强,这也解释了抑制剂的较高活性。其余抑制剂的结构改变都会使氢键的减少或减弱,导致抑酶活性下降。抑制剂4-8虽然体现出较好的抑酶活性,但是对结核杆菌却是无效的。化合物可能无法在细胞内部积累,化合物可能无法进入到结核菌内部或者被主动外排,造成活性丧失。到目前为止,所有泛酸合成酶抑制剂的报道都局限于对酶的抑制。而那些抑酶活性很好的泛酸合成酶抑制剂却很少有报道其抗结核活性,这也从另一个方面说明目前泛酸合成酶可能不是一个抗结核的理想靶点。
[Abstract]:This article contains two parts. The first part of this paper is the design, synthesis and anti-schistosome activity in the first part of this paper, which is an acute and chronic parasitic disease caused by the schistosome. The main insect species of the parasitic human body are Schistosoma japonicum, Schistosoma mansoni and Schistosoma japonicum. PZQ is the only special drug used for the treatment of schistosomiasis in Japan. It is inevitable that the excessive dependence on the oxycodone is a potential hazard. The antimalarial drug was found to have a high killing effect on the worm and the adult, but the clinical study found that it was not good for the treatment of schistosomiasis. In order to reduce the central nervous side effect of the alpha-fluorobenzene, a new structural framework is constructed, and an oxygen methylene group is inserted into the side chain of the methyl fluoride. The structure-effect relationship was studied by transforming different amino and aromatic rings. A total of 52 new compounds were synthesized, and the LD50 of 24 compounds in vitro was less than 10. m The LD50 of the compound QC010105 was less than 10. m u.M. The activity of the compound QC010105 was comparable to that of the anti-schistosome and the adult in vitro. Although the compounds are not good in in vivo experiments, it is proved that the compounds are a class of anti-schistosome compounds that are worthy of further study. The next study can be carried out for the modification of the group of ditrifluoromethyl and the like, and is expected to obtain a new anti-schistosome new drug with better activity. The second part of this paper is the design, synthesis and activity of pantothenic acid synthetase inhibitor. The increasing number of drug-resistant tuberculosis cases and the prevalence of AIDS have led to the development of anti-tuberculosis drugs as one of the hot spots in the research and development of new drugs. Although two anti-drug-resistant tuberculosis drugs have been approved for listing in the last three years, the form of the treatment of drug-resistant tuberculosis is still serious, and new drug-resistant bacteria have been found, and XDR-TB is still not available for treatment. The pantothenic acid synthetase encoded by the pan C gene is a potential target for anti-tuberculosis drugs, which is completely different from the target target of the first-line anti-tuberculosis drugs which are widely used at present, so that the cross resistance can not be caused. The amount of pantothenic acid synthetase inhibitor currently found is limited and all the inhibitors are almost ineffective for tubercle bacillus. In this paper, 10 new inhibitors of pantothenic acid synthase were synthesized in the form of an intermediate of the catalytic reaction of pantothenic acid synthase. All the inhibitors maintained the same chiral conformation as the reaction intermediate catalyzed by the pantothenic acid synthase at the C2 position, and different inhibitors were obtained for the transformation of the Pantic acid portion, the sugar ring portion, and the base portion, respectively. The inhibitor 4-8 was determined to inhibit the activity of the enzyme, and the inhibition constant was obtained, and the results were explained using the computer-aided design. and then the activity of the anti-tubercle bacillus is evaluated. All of the inhibitors are competitive inhibitors of the substrate pantate, and the activity of the best inhibitor 4 relative to pantate is 0.27 to 0.04. m u.M, and the difference reported in the literature is comparable to the heterogeneous mixture 3j (Ki is 0.3. mu.M). Although the method of determining Ki is different, it is also indicated that the chiral effect of the C2-position of the pantic acid fragment is not large. By computer simulation of the docking test, we found that the inhibitor 4 interacts with a total of 9 hydrogen bonds in the protein, and the effect is strong, which also explains the higher activity of the inhibitor. The structural changes of the rest of the inhibitor will decrease or decrease the hydrogen bond, resulting in a decrease in the enzyme-inhibiting activity. Although the inhibitor 4-8 shows a better enzyme-inhibiting activity, it is not effective for the tubercle bacillus. The compound may not accumulate inside the cell, and the compound may not be able to enter or be actively discharged into the tubercle bacillus, resulting in loss of activity. So far, the reports of all pantothenic acid synthetase inhibitors are limited to the inhibition of the enzyme. However, the anti-tuberculosis activity of the pantothenic acid synthetase inhibitor which is very good in the enzyme-inhibiting activity is rarely reported, which also shows that the present pantothenic acid synthetase may not be an ideal target for anti-tuberculosis.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R914;R96
本文编号：2366101
[Abstract]:This article contains two parts. The first part of this paper is the design, synthesis and anti-schistosome activity in the first part of this paper, which is an acute and chronic parasitic disease caused by the schistosome. The main insect species of the parasitic human body are Schistosoma japonicum, Schistosoma mansoni and Schistosoma japonicum. PZQ is the only special drug used for the treatment of schistosomiasis in Japan. It is inevitable that the excessive dependence on the oxycodone is a potential hazard. The antimalarial drug was found to have a high killing effect on the worm and the adult, but the clinical study found that it was not good for the treatment of schistosomiasis. In order to reduce the central nervous side effect of the alpha-fluorobenzene, a new structural framework is constructed, and an oxygen methylene group is inserted into the side chain of the methyl fluoride. The structure-effect relationship was studied by transforming different amino and aromatic rings. A total of 52 new compounds were synthesized, and the LD50 of 24 compounds in vitro was less than 10. m The LD50 of the compound QC010105 was less than 10. m u.M. The activity of the compound QC010105 was comparable to that of the anti-schistosome and the adult in vitro. Although the compounds are not good in in vivo experiments, it is proved that the compounds are a class of anti-schistosome compounds that are worthy of further study. The next study can be carried out for the modification of the group of ditrifluoromethyl and the like, and is expected to obtain a new anti-schistosome new drug with better activity. The second part of this paper is the design, synthesis and activity of pantothenic acid synthetase inhibitor. The increasing number of drug-resistant tuberculosis cases and the prevalence of AIDS have led to the development of anti-tuberculosis drugs as one of the hot spots in the research and development of new drugs. Although two anti-drug-resistant tuberculosis drugs have been approved for listing in the last three years, the form of the treatment of drug-resistant tuberculosis is still serious, and new drug-resistant bacteria have been found, and XDR-TB is still not available for treatment. The pantothenic acid synthetase encoded by the pan C gene is a potential target for anti-tuberculosis drugs, which is completely different from the target target of the first-line anti-tuberculosis drugs which are widely used at present, so that the cross resistance can not be caused. The amount of pantothenic acid synthetase inhibitor currently found is limited and all the inhibitors are almost ineffective for tubercle bacillus. In this paper, 10 new inhibitors of pantothenic acid synthase were synthesized in the form of an intermediate of the catalytic reaction of pantothenic acid synthase. All the inhibitors maintained the same chiral conformation as the reaction intermediate catalyzed by the pantothenic acid synthase at the C2 position, and different inhibitors were obtained for the transformation of the Pantic acid portion, the sugar ring portion, and the base portion, respectively. The inhibitor 4-8 was determined to inhibit the activity of the enzyme, and the inhibition constant was obtained, and the results were explained using the computer-aided design. and then the activity of the anti-tubercle bacillus is evaluated. All of the inhibitors are competitive inhibitors of the substrate pantate, and the activity of the best inhibitor 4 relative to pantate is 0.27 to 0.04. m u.M, and the difference reported in the literature is comparable to the heterogeneous mixture 3j (Ki is 0.3. mu.M). Although the method of determining Ki is different, it is also indicated that the chiral effect of the C2-position of the pantic acid fragment is not large. By computer simulation of the docking test, we found that the inhibitor 4 interacts with a total of 9 hydrogen bonds in the protein, and the effect is strong, which also explains the higher activity of the inhibitor. The structural changes of the rest of the inhibitor will decrease or decrease the hydrogen bond, resulting in a decrease in the enzyme-inhibiting activity. Although the inhibitor 4-8 shows a better enzyme-inhibiting activity, it is not effective for the tubercle bacillus. The compound may not accumulate inside the cell, and the compound may not be able to enter or be actively discharged into the tubercle bacillus, resulting in loss of activity. So far, the reports of all pantothenic acid synthetase inhibitors are limited to the inhibition of the enzyme. However, the anti-tuberculosis activity of the pantothenic acid synthetase inhibitor which is very good in the enzyme-inhibiting activity is rarely reported, which also shows that the present pantothenic acid synthetase may not be an ideal target for anti-tuberculosis.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R914;R96
【参考文献】
相关硕士学位论文 前1条
1 龚立康;以泛酸合成酶为靶点的抗结核药物筛选模型的建立和应用[D];中国协和医科大学;2006年
，本文编号：2366101
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