【作者】 孙琦；

【导师】 杨晓虹；

【作者基本信息】 吉林大学 ， 药物化学， 2014， 硕士

【摘要】 菌群生长过程中细菌能不断产生化学信号分子并分泌到周围环境中，当信号分子的数量达到一定阈值时，可调控菌体相关基因的表达如生物被膜的形成、生物发光等，以适应环境的变化，这种现象被称为细菌群体感应（quorumsensing,QS）。目前已经在包括铜绿假单胞菌、大肠杆菌等致病菌在内的50多种细菌中发现了群体感应现象，通过抑制细菌的群体感应系统，可以阻断不良基因的表达。细菌群体感应抑制剂通过阻断病原菌有害基因的表达,从而使其失去致病能力，并不干扰细菌的正常生理活动，因此被视为抗菌药物发展的新方向。本文拟合成新型细菌群体感应抑制剂，用于治疗耐药性的革兰氏阴性菌所致疾病。群体感应抑制剂研究中最具成效的是N-酰基高丝氨酸内酯(N-Acyl homoserinelactones, AHLs)信号分子介导的抑制剂，即AHLs类似物。因此，本文拟对AHLs信号分子的群体感应系统设计QS系统抑制剂。本文采用具有细菌群体感应调控系统的紫色色杆菌作为模型菌，用以研究细菌群体感应抑制剂。通过对已报道抑制剂的构效关系进行分析，设计了一系列N-磺酰基高丝氨酸内酯类化合物。首先，本文保留S型高丝氨酸内酯母核不变，在母核与酰胺基之间引入可提高疏水性、生物活性广泛的苯磺酰基，同时在苯磺酰基侧链上连接五元、六元芳香族杂环及苯乙基，以探究其对群体感应抑制活性的影响。按照这种设计思路，从简单易得的原料出发，经多步反应，共合成33个目标化合物，所合成的化合物结构均经MS、1H-NMR确证。利用目标化合物在紫色色杆菌CV026中对紫色杆菌素的抑制作用来评价其生物活性，其中16个化合物具有抑制作用,化合物7-9的抑制活性最好。初步的构效关系研究表明，1）化合物的N-磺酰基高丝氨酸内酯侧链尾端连接五元芳香族杂环时活性好于连接苯乙基。2）五元芳香族杂环上连吸电子基的化合物活性优于连接供电子基。3）连接噻唑基团时3位为吸电子基的化合物活性最好，5位次之。抑制活性最好的化合物7-9有进一步的研究价值。更多还原

【Abstract】 In the growth process of bacteria, they can produce chemical signal moleculesand secret them into the surrounding environment. When the number of signalmolecules reaches to a certain threshold, the expression of related genes will beregulated to adapt to the environmental changes such as the biofilm formation,bioluminescent, et al. This phenomenon is called quorum sensing (QS). So far, QShas been discovered in more than50bacteria, including P.aeruginosa and E.coil.Inhibiting the quorum sensing system can restrain the expression of harmful genes.QS inhibitors make pathogens lose pathogenicity by blocking the expression ofharmful genes, they do not interfere with the normal physiological activity of bacteria,which is regarded as a new direction of the antimicrobial drugs’ development. Thepurpose of this paper is to synthesize a new type of bacterial quorum sensinginhibitors, which can be used for the treatment of diseases caused by resistantgram-negative bacteria. The AHL analogues which have the most effective study,inhibit QS system mediated with N-acylhomoserine lactones (AHLs) molecules. Thetarget of our project is to design QS inhibitors against the quorum sensing system ofAHLs signal molecules.In this paper, we researched QS inhibitors using C.violaceum as bacterial model.N-sulfonyl homoserine lactone derivatives have been designed by thestructure-activity relationship analysis. First of all, we reserved the S-type homoserinelactone nucleus, benzenesulfonyl was introduced between nucleus and amide group,which could improve hydrophobicity and had broad biological activity. In order toexplore the effect to QS inhibitory activity, a series of five-, six-memebered aromaticheterocyclics and phenethyl groups were connected after benzenesulfonyl side chain.Starting from the simple and available materials, through multistep reaction,33target compounds were synthesized. The structures of all the compounds wereidentified by methods of MS and1H-NMR. The biological activities of target compounds were evaluated through the violacein inhibition in Chromobacteriumviolaceum CV026.16compounds had antagonist effect and compound7-9showedthe best antagonist activity. Studies of structure-activity relationship showed thatN-acylhomoserine lactone compounds with a five-membered aromatic heterocyclicsubstituted in side chain showed better activity than those substituted by phenethylgroups on the same position. Five-membered aromatic compounds which connectedelectron withdrawing group had better inhibitory activity than those connectedelectron donating group. Further analysis of thiazolyl groups showed that orthosubstituted thiazolyl groups with electron withdrawing group were superior the paraand meta substituted thiazolyl groups. The inhibitory activity of compound7-9wasthe best, which could be used for further development.更多还原