氨基噻唑类化合物的合成及其生物活性研究

发布时间：2018-06-15 04:45

本文选题：噻唑 + 线虫　；参考：《华东理工大学》2017年硕士论文

【摘要】：噻唑类化合物以其独特的含氮、硫杂环结构和多样的生物活性,广泛应用于医药、农药、精细化工等领域。在前期工作中,课题组合成得到了具有一定杀线虫活性的噻唑类化合物P6及P12。本论文在此结构基础上进行进一步的结构衍生,寻找具有更高杀线虫活性的化合物并进一步拓展其他生物活性。基于对化合物P6及P12的结构分析,设计合成了 29个氨基噻唑类化合物并进行了线虫活性测试。虽然衍生合成的化合物的杀线虫活性没有提升,但在活性筛选的过程中发现其对多粘菌素B具有良好抗菌增效活性,进而详细研究了其抗菌及抗菌增效活性。活性测试结果表明,化合物能够增效多粘菌素B对测试菌株(鲍曼不动杆菌ATCC19606和肺炎克雷伯菌SIPI-KPN-1712)的抗菌活性,且当噻唑上的氨基被4-三氟甲基苯基取代时,抗菌增效作用较好。以4-三氟甲基苯亚氨基噻唑类化合物为结构骨架,在噻唑环4-位引入不同的芳环及芳杂环,合成了 19个目标化合物。抗菌增效活性测试表明,当化合物浓度为4 μgml-1时,多数化合物可使多粘菌素B的最小抑菌浓度(MIC)降低。B6与B16在4 μg ml-1时分别可使多粘菌素B对鲍曼不动杆菌ATCC19606的MIC从1 μgml-1降低至0.125 μgml-1和0.0625 μg ml-1,对肺炎克雷伯菌SIPI-KPN-1712的MIC从32 μg ml-1降低至1 μg ml-1和4 μgml-1。时间-杀菌曲线测试结果表明,相比于单独用药,联合用药能够减少多粘菌素B的用量并在更短时间内达到持续杀菌效果。同时,进一步研究表明该系列化合物对革兰氏阳性菌也具有良好的杀菌活性。为了改善其水溶性,基于活性较好的4-三氟甲基苯亚氨基噻唑类化合物,合成了 5个该类化合物的盐,及一个磷酸酯前药。测试了化合物的水溶性及抗菌增效活性。结果发现目标盐类化合物虽保持了原结构对多粘菌素B抗鲍曼不动杆菌的增效活性,但水溶性并无明显提升;磷酸酯前药的水溶性得到了明显改善,在纯水中的饱和溶解度为134.40ppm,在体外实验中没有表现出抗菌增效活性,体内药效试验正在进行中。
[Abstract]:Thiazole compounds are widely used in the fields of medicine, pesticides and fine chemicals, due to their unique nitrogen, sulfur heterocyclic structures and various biological activities. In the early work, the thiazole compounds have been combined to obtain a thiazole compound with certain nematide activity P6 and P12.. The compounds with higher nematode activity and further development of other biological activities. Based on the structural analysis of P6 and P12, 29 amino thiazole compounds were designed and synthesized and the nematode activity was tested. Although the nematode activity of the compounds derived from the derivatives did not increase, they were found in the process of screening. Polymyxin B has good antibacterial synergistic activity, and then studies its antibacterial and antibacterial activity in detail. The activity test results show that the compound can increase the antibacterial activity of polymyxin B to test strains (Acinetobacter Bauman ATCC19606 and Klebsiella pneumoniae SIPI-KPN-1712), and the amino group on thiazole is obtained by 4- three fluoromethyl phenyl. 4- three fluoromethyl benzothiazoles were used as the structural skeleton, and different aromatic rings and aromatic heterocyclic rings were introduced at the 4- site of thiazole ring, and 19 target compounds were synthesized. The antibacterial synergistic activity test showed that when the concentration of the compound was 4 u gml-1, the minimum inhibitory concentration of polymyxin B (M IC) reduced.B6 and B16 at 4 mu g ml-1, respectively, to reduce the MIC from 1 gml-1 to 0.125 mu gml-1 and 0.0625 mu g ml-1, respectively. The results of the reduction of Klebsiella pneumoniae from 32 Mu to 1 mu and 4 micron time - bactericidal curve test showed that compared with the individual drug use, The combined drug can reduce the dosage of polymyxin B and achieve sustained bactericidal effect in a shorter time. At the same time, further studies have shown that the series of compounds also have good bactericidal activity for Gram-positive bacteria. In order to improve their water solubility, 5 kinds of compounds have been synthesized based on the better activity of three fluoromethyl benzothiazoles. The water solubility and antibacterial synergistic activity of the compound were tested. The results showed that the water solubility of the target salt compound had not increased significantly, although the target salt compound kept the synergistic activity of the original structure against the polymyxin B against Acinetobacter Bauman, and the water solubility of the phosphate ester was obviously improved and satiated in pure water. And solubility of 134.40ppm, in vitro experiments showed no antibacterial synergistic effect, in vivo pharmacodynamic test is in progress.
【学位授予单位】：华东理工大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：TQ252.5

【参考文献】