芳基取代的螺环吲哚二酮哌嗪类化合物的合成及其抑菌活性研究

发布时间：2018-04-24 17:15

本文选题：spirotryprostatins + 芳环取代　；参考：《陕西科技大学》2017年硕士论文

【摘要】：芳基取代的螺环吲哚二酮哌嗪类化合物是螺环吲哚二酮哌嗪类化合物的重要组成部分,而螺环吲哚二酮哌嗪类化合物中主要以spirotryprostatin类生物碱为代表。研究发现该类化合物具有很好的生理和药理活性,尤其对细胞周期有较好的抑制活性。因此,spirotryprostatin类生物碱可以作为新药物筛选的先导化合物。本论文对spirotryprostatin类生物碱的骨架进行了修饰,首次合成了一系列芳基取代的螺环吲哚二酮哌嗪类化合物并对其进行了结构鉴定和抑菌活性研究。本论文以甘氨酸和靛红为反应原料,分别通过两步反应得到12种席夫碱化合物(偶极体)和13种3-芳亚甲基-2-吲哚酮化合物(亲偶极体),选用单一的亲偶极体3-苯亚甲基-2-吲哚酮分别和12种席夫碱偶极体化合物在手性配体(S)-TF-BiphamPhos和AgOAc催化下发生1,3-偶极环加成反应得到12种螺环吡咯烷中间体,螺环吡咯烷中间体再与Fmoc-L-pro-Cl发生酰胺化反应,然后经有机碱催化脱去保护基并诱导自发关环得到目标产物9a-9e,这5个化合物皆为新化合物。所有化合物经核磁1H-NMR、13C-NMR、红外光谱、元素分析和HRMS等手段进行结构表征,并通过2D NMR和X-ray衍射确定了中间体和目标产物的立体构型。在抑菌活性实验中,共选用4株细菌,分别是两株革兰氏阳性菌-金黄色葡萄球菌(Staphy lococcus aureus)和乳酸链球菌(Streptococcus lactis),两株革兰氏阴性菌-大肠杆菌(Escherichia coli)和绿脓杆菌(Pseudomonas aeruginosa);10株植物病原真菌,分别是小麦赤霉病菌(Fusarium graminearum)、番茄灰霉病菌(Botrytis cinerea)、苹果树腐烂病菌(Valsa mali)、烟草赤星病菌(Alternaria alternate)、白菜黑斑病菌(Alternaria brassicae)、玉米大斑病菌(Setosphaeria turcica)、芍药炭疽病菌(Peony anthracnose)、油菜菌核病菌(Sclerotinia sclerotiorum)、辣椒炭疽病菌(Phytophthora capsici)、葡萄炭疽病菌(Colletotrichum gloeosporioides)。初步的结果显示,中间体化合物和目标产物都具有一定的抗菌活性,而且目标产物的活性优于相对应的中间体化合物,所有的化合物抗细菌的活性普遍优于抗真菌的活性。这为进一步研究该类化合物的抑菌活性的机理提供了一定的理论基础。
[Abstract]:Aryl substituted spiroindole piperazine compounds are important components of spirocyclic indoledione piperazine compounds, while spirocyclic indoledione piperazine compounds are mainly represented by spirotryprostatin alkaloids. It was found that these compounds had good physiological and pharmacological activities, especially on cell cycle inhibition. Therefore, spirotryprostatin alkaloids can be used as lead compounds for screening new drugs. In this paper, the skeleton of spirotryprostatin alkaloids was modified and a series of aryl substituted spiroindole piperazine compounds were synthesized for the first time. In this thesis, glycine and indirubin were used as raw materials. Twelve Schiff base compounds (dipoles) and 13 3-arylene methylene-2-indolone compounds (dipolar dipolar compounds) were obtained by two-step reaction respectively, and 12 Schiff bases were obtained using a single dipolar compound, 3-phenylene methyl-2-indole ketone and 12 Schiff bases, respectively. Twelve kinds of spirocyclic pyrrolidine intermediates were synthesized from dipolar compounds catalyzed by chiral ligand Schi-TF-BiphamPhos and AgOAc. The intermediate of spirocyclic pyrrolidine was amidation with Fmoc-L-pro-Cl, then the protective group was removed by organic base and the target product 9a-9e was obtained by spontaneous closing of the ring. The five compounds were all new compounds. All the compounds were characterized by 1H-NMR-13C-NMR-IR, IR, elemental analysis and HRMS. The steric configurations of the intermediates and the target products were determined by 2D NMR and X-ray diffraction. Four strains of bacteria, Staphy lococcus aureus, Streptococcus lactis, Escherichia coli (Escherichia coli) and Pseudomonas aeruginosa (10 strains of Pseudomonas aeruginosa) were selected in the experiment. They are Fusarium graminearum, Botrytis cinereaer, Valsa malium, Alternaria alternateae, Alternaria brassicaeae, Setosphaeria cicaeae, Peony racnoseet, Sclerotinia sclerotiorumum, capsicum. Phytophthora capsicii, Colletotrichum gloeosporioides. The preliminary results showed that both the intermediates and the target products had certain antibacterial activity, and the activity of the target products was better than that of the corresponding intermediates, and the antimicrobial activities of all the compounds were generally superior to those of the antifungal compounds. This provides a theoretical basis for further study on the mechanism of bacteriostatic activity of this kind of compounds.
【学位授予单位】：陕西科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O626

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