本文選題：工藝優(yōu)化 + 硝唑尼特衍生物��； 參考：《山東大學》2017年碩士論文

【摘要】：硝坐尼特(Nitazoxanid,NTZ)是一種廣譜抗微生物藥物,屬于硝基噻唑類化合物,能夠治療多種類型的感染,包括寄生蟲,細菌,病毒等,也可用于治療艾滋病(AIDS)、慢性肝炎、癌癥等,同時也能抑制生物膜的形成。由于NTZ這種廣泛的生物活性和良好的市場應(yīng)用前景等,對其合成路線進行深入研究,研發(fā)一種成本低、收率好、環(huán)境友好的合成路線具有廣泛的經(jīng)濟和社會效益。本論文在總結(jié)已有合成路線的基礎(chǔ)上提出了一種全新合成NTZ的方法:用三甲氧基磷、碘和三乙胺作為反應(yīng)試劑,利用一步法合成了硝唑尼特。對反溶劑、堿的種類、物料配比、溫度等條件進行優(yōu)化,最終確定了一條最優(yōu)的合成路線。以收率76%,純度83.7%的結(jié)果得到了目標化合物硝唑尼特。研究表明NTZ衍生物和NTZ一樣也具有廣譜的抗感染活性,尤其在抗菌和抗寄生蟲方面表現(xiàn)出了較好的活性。NTZ的作用機制不同于其他硝基化合物,它通過作用于丙酮酸-鐵氧化還原蛋白酶起作用。因此本文也對NTZ進行了合理衍生化,設(shè)計了兩個系列針對酮酸-鐵氧化還原白酶的抑制劑,并對其進行初步的活性篩選。具體地,利用藥物化學的多種藥物設(shè)計策略結(jié)合計算機輔助藥物設(shè)計,設(shè)計、合成出了系列Ⅰ和系列Ⅱ結(jié)構(gòu)全新的NTZ衍生物,進行了初步的體外抗菌和抗弓形蟲活性篩選,探討了這些衍生物的構(gòu)效關(guān)系。從中發(fā)現(xiàn)了部分化合物XQH-3-6,XQH-3-7和XQH-2-92具有較好的抗菌活性,尤其對變形鏈球菌的作用活性較好�；衔颴QH-2-88.XQH-2-91和XQH-2-96具有較好的抗弓形蟲活性,這些化合物可作為先導(dǎo)結(jié)構(gòu)進行下一步更深入的研究,從而發(fā)現(xiàn)活性和成藥性更好、毒副作用更低、選擇性史強的化合物。
[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.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R914;R96

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