新型氮唑类衍生物的合成及活性研究

发布时间：2018-01-29 17:35

本文关键词： 氮唑类合成、抗真菌活性构效关系　出处：《第二军医大学》2017年硕士论文　论文类型：学位论文

【摘要】：近年来,随着生物科技的突飞猛进,放疗、化疗、介入等方法手段大量运用于治疗癌症、器官移植以及艾滋病患者,从而迫使免疫抑制剂、广谱抗生素、皮质激素等药物在临床上被大量使用。正是由于这些技术的广泛使用,使得深部真菌感染在临床治疗中呈现出易多发,且迅速上升的趋势,越来越严重地威胁着人类的生命健康,目前已经是第三大感染性疾病。因此,对抗真菌药物的深入研究日益迫切,也逐渐被人们所重视。二硫代胺基甲酸酯类化合物(DTCs)具有多种生物学活性,其高效低毒及易合成等优点使其成为当前药物化学领域研究的热点问题。本课题通过分析氮唑类抗真菌药物的构效关系及其作用机制设计了如下化合物:保留主要药效基团三唑环、叔醇结构和2,4-二氟苯基的条件下,利用DTC合成法引入胺基二硫代甲酸酯的同时分别引入不同结构的取代苄基侧链,共合成、设计了44个1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-取代-2-丙醇类化合物。所有目标化合物经核磁共振氢谱、质谱等手段确证结构。本课题体外抑菌活性测试是参考美国临床实验室标准委员会(NCCLS)提出的标准化抗真菌敏感性的实验方法,对8种真菌包括:白念珠菌(ATCC14053)、薰烟曲霉菌、近平滑念珠菌、新生隐球菌(ATCC32609)、光滑念珠菌、红毛癣菌、石膏样小孢子菌和SCZ20352,并以两性霉素B、氟康唑、活立康唑、酮康唑、伊曲康唑、特比萘酚作为阳性对照药。初步的体外抑菌实验结果表明:大部分化合物对出烟曲霉菌和小孢子菌以外的6种真菌都有一定的抑菌活性。其中化合物1c-d,1r-s,2a-s均有较好的体外抑菌活性,且很明显要高于对照药品的抑菌活性,如:氟康唑、两性霉素B、伊曲康唑、特比萘芬等。此外,在侧链氮原子上连接异丙胺的一类化合物其活性要高于同位置连结烯丙胺的化合物,故值得进行下一步深入研究。
[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.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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