硝唑尼特合成新工艺及其衍生物的设计、合成和初步生物活性研究

发布时间：2018-05-18 18:42

本文选题：工艺优化 + 硝唑尼特衍生物　；参考：《山东大学》2017年硕士论文

【摘要】：硝坐尼特(Nitazoxanid,NTZ)是一种广谱抗微生物药物,属于硝基噻唑类化合物,能够治疗多种类型的感染,包括寄生虫,细菌,病毒等,也可用于治疗艾滋病(AIDS)、慢性肝炎、癌症等,同时也能抑制生物膜的形成。由于NTZ这种广泛的生物活性和良好的市场应用前景等,对其合成路线进行深入研究,研发一种成本低、收率好、环境友好的合成路线具有广泛的经济和社会效益。本论文在总结已有合成路线的基础上提出了一种全新合成NTZ的方法:用三甲氧基磷、碘和三乙胺作为反应试剂,利用一步法合成了硝唑尼特。对反溶剂、碱的种类、物料配比、温度等条件进行优化,最终确定了一条最优的合成路线。以收率76%,纯度83.7%的结果得到了目标化合物硝唑尼特。研究表明NTZ衍生物和NTZ一样也具有广谱的抗感染活性,尤其在抗菌和抗寄生虫方面表现出了较好的活性。NTZ的作用机制不同于其他硝基化合物,它通过作用于丙酮酸-铁氧化还原蛋白酶起作用。因此本文也对NTZ进行了合理衍生化,设计了两个系列针对酮酸-铁氧化还原白酶的抑制剂,并对其进行初步的活性筛选。具体地,利用药物化学的多种药物设计策略结合计算机辅助药物设计,设计、合成出了系列Ⅰ和系列Ⅱ结构全新的NTZ衍生物,进行了初步的体外抗菌和抗弓形虫活性筛选,探讨了这些衍生物的构效关系。从中发现了部分化合物XQH-3-6,XQH-3-7和XQH-2-92具有较好的抗菌活性,尤其对变形链球菌的作用活性较好。化合物XQH-2-88.XQH-2-91和XQH-2-96具有较好的抗弓形虫活性,这些化合物可作为先导结构进行下一步更深入的研究,从而发现活性和成药性更好、毒副作用更低、选择性史强的化合物。
[Abstract]:Nitazoxanid (NTZ) is a broad-spectrum anti microbial drug, belonging to the nitrothiazole compound, can treat various types of infection, including parasites, bacteria, viruses, and can also be used to treat AIDS (AIDS), chronic hepatitis, cancer and so on, and can also inhibit the formation of biofilm. Because of the extensive biological activity and good of NTZ The synthetic route of a low cost, good yield and environmentally friendly synthetic route has extensive economic and social benefits. On the basis of summarizing the existing synthetic routes, a new formula for synthesizing NTZ is proposed in this paper: tri methoxy phosphorus, iodine and three ethylamine are used as the reaction test. A one-step method was used to synthesize nitazolidic. The best synthesis route was determined for the anti solvent, the type of alkali, the material ratio and the temperature. The target compound nitrazole was obtained by the yield of 76% and the purity of 83.7%. The study showed that the NTZ derivatives have broad spectrum of anti infective activity as well as NTZ. The mechanism of the better active.NTZ is different from other nitro compounds in the aspects of antibacterial and anti parasite. It acts on pyruvate - iron oxidation-reduction protease. Therefore, this paper also made a reasonable derivatization of NTZ and designed two series of inhibitors for ketoacid - iron redox white enzyme. Preliminary activity screening. Specifically, a series of new NTZ derivatives of series I and Series II structures have been synthesized using a variety of drug design strategies in the combination of drug chemistry and computer aided drug design. Preliminary antibacterial and anti Toxoplasma activity screening in vitro are carried out, and the structure-activity relationships of these derivatives are discussed. Some of these derivatives have been discovered. Compounds XQH-3-6, XQH-3-7 and XQH-2-92 have good antibacterial activity, especially to Streptococcus mutans. Compounds XQH-2-88.XQH-2-91 and XQH-2-96 have good Antitoxoplasma activity. These compounds can be used as pilot structures for further study on the next step, thus finding the better activity and drug resistance and toxic side effects. Lower, highly selective compounds.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

【相似文献】