本文關鍵詞： 氮唑類 合成、抗真菌活性 構效關系　出處：《第二軍醫(yī)大學》2017年碩士論文　論文類型：學位論文

【摘要】：近年來,隨著生物科技的突飛猛進,放療、化療、介入等方法手段大量運用于治療癌癥、器官移植以及艾滋病患者,從而迫使免疫抑制劑、廣譜抗生素、皮質激素等藥物在臨床上被大量使用。正是由于這些技術的廣泛使用,使得深部真菌感染在臨床治療中呈現(xiàn)出易多發(fā),且迅速上升的趨勢,越來越嚴重地威脅著人類的生命健康,目前已經是第三大感染性疾病。因此,對抗真菌藥物的深入研究日益迫切,也逐漸被人們所重視。二硫代胺基甲酸酯類化合物(DTCs)具有多種生物學活性,其高效低毒及易合成等優(yōu)點使其成為當前藥物化學領域研究的熱點問題。本課題通過分析氮唑類抗真菌藥物的構效關系及其作用機制設計了如下化合物:保留主要藥效基團三唑環(huán)、叔醇結構和2,4-二氟苯基的條件下,利用DTC合成法引入胺基二硫代甲酸酯的同時分別引入不同結構的取代芐基側鏈,共合成、設計了44個1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代-2-丙醇類化合物。所有目標化合物經核磁共振氫譜、質譜等手段確證結構。本課題體外抑菌活性測試是參考美國臨床實驗室標準委員會(NCCLS)提出的標準化抗真菌敏感性的實驗方法,對8種真菌包括:白念珠菌(ATCC14053)、薰煙曲霉菌、近平滑念珠菌、新生隱球菌(ATCC32609)、光滑念珠菌、紅毛癬菌、石膏樣小孢子菌和SCZ20352,并以兩性霉素B、氟康唑、活立康唑、酮康唑、伊曲康唑、特比萘酚作為陽性對照藥。初步的體外抑菌實驗結果表明:大部分化合物對出煙曲霉菌和小孢子菌以外的6種真菌都有一定的抑菌活性。其中化合物1c-d,1r-s,2a-s均有較好的體外抑菌活性,且很明顯要高于對照藥品的抑菌活性,如:氟康唑、兩性霉素B、伊曲康唑、特比萘芬等。此外,在側鏈氮原子上連接異丙胺的一類化合物其活性要高于同位置連結烯丙胺的化合物,故值得進行下一步深入研究。
[Abstract]:In recent years, with the rapid development of biotechnology, radiotherapy, chemotherapy, intervention and other methods are widely used in the treatment of cancer, organ transplantation and AIDS patients, thus forcing immunosuppressive agents, broad-spectrum antibiotics. Corticosteroids and other drugs are widely used in clinic. Because of the wide use of these techniques, deep fungal infections in the clinical treatment is prone to multiple, and rapidly rising trend. More and more serious threats to human life and health, is now the third largest infectious disease. Therefore, the in-depth study of antifungal drugs is increasingly urgent. Dithiocarbamate (DTCs) has many biological activities. Because of its high efficiency, low toxicity and easy to synthesize, it has become a hot topic in the field of pharmaceutical chemistry. The following compounds were designed by analyzing the structure-activity relationship and the mechanism of azazole antifungal drugs. The main effector group triazole ring was retained. Under the conditions of tertiary alcohol structure and 2o 4- difluorophenyl, the DTC synthesis method was used to introduce amino dithiocarbamate and different substituted benzyl side chains, respectively, for the co-synthesis of amino dithiocarbamate. A total of 44 4-triazole-1-triazole-2-difluorophenyl-3-substituted -2-propanol compounds have been designed. All the target compounds have been characterized by nuclear magnetic resonance spectroscopy (HNMR). The in vitro antimicrobial activity test is a standardized antifungal sensitivity test proposed by the American Committee of Clinical Laboratory Standards (NCCLSs). For 8 species of fungi, they are Candida albicans ATCC 14053, Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans ATCC 32609, Candida albicans and Trichophyton rubrum. Gypsum like microsporum and SCZ 20352, and with amphotericin B, fluconazole, lipoponazole, ketoconazole, itraconazole. Terbinol was used as a positive control drug. The results of in vitro bacteriostatic test showed that most of the compounds had certain antibacterial activity against 6 kinds of fungi except Aspergillus fumigatus and microsporum, among which compound 1c-d. 1r-sf2a-s have better antibacterial activity in vitro and are obviously higher than those of control drugs, such as fluconazole, amphotericin B, itraconazole, terbinafine, etc. The activity of a class of compounds with isopropylamine attached to side chain nitrogen atoms is higher than that of allylamine in the same position, so it is worthy of further study.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R914;R96

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