喹啉酮类衍生物的合成及其抗菌与抗炎活性研究

发布时间：2018-05-04 17:15

本文选题：喹啉酮 + 氨基胍　；参考：《延边大学》2017年硕士论文

【摘要】：21世纪以来,细菌耐药性问题在全球范围内都广泛出现,并且日益严重。根据英国首相经济学顾问的调查报告,如果细菌耐药性不加遏制,到2050年全球每年将有1000万人死于耐药菌感染,每年的经济损失将高达100万亿美元。在中国,细菌耐药问题同样严重。遗憾的是,新型抗菌药物的研发并没有伴随着耐药性细菌的增加而增加。多药耐药的感染加上缺乏新的抗菌药物,导致临床医生开始重新考虑使用多黏菌素作为最后的治疗手段,而多黏菌素由于存在神经毒性和肾毒性,已经多年未在临床中使用。因此,寻找具有新结构和新靶点的新型抗菌药物已迫在眉睫。炎症是一种常见的病理生理现象,涉及许多疾病,是身体对有害刺激最原始的保护性反应。炎症在过敏反应、自身免疫性疾病和器官移植排斥等方面严重威胁着人类的健康。非甾体抗炎药在治疗急性和慢性炎症方面的应用已非常普遍,但是长期服用会产生一些不良反应,如骨组织损伤、胃肠道损伤、肝脏损伤、中毒性肾损伤。因此开发新型安全的抗炎药物具有一定的实际意义。研究显示,多数含有喹啉结构的化合物具有不同的生物活性,包括抗微生物、抗肿瘤、抗HIV、抗炎、抗疟疾等;氨基胍与腙类化合物也表现出良好的抗菌与抗炎活性。本文作者通过分子拼接的方法,以6-羟基-3,4-二氢喹啉酮为母体,引入氨基胍与腙类结构,设计合成了三个系列5a-5m,6a-6h,7a、7b和7g共24个喹啉酮类化合物,并通过体外抗菌实验和二甲苯诱导小鼠耳肿胀实验测定化合物的抗菌与抗炎活性。三个系列化合物中,只有5a-5m系列化合物有较好的抗菌活性,且对革兰氏阳性菌和真菌的抑制作用优于革兰氏阴性菌,MIC值为1-64 μg/mL;而对革兰氏阴性菌除了对1924和2421有较好的抗菌抑制作用外,对其余革兰氏阴性菌几乎都没有抑制效果,5系列化合物对临床多重耐药菌也有较强的抗菌效果,MIC值为1-64μg/mL。其中,化合物5c、5d和5k的活性最好,其MIC值均达到1μg/mL。5系列化合物对耐甲氧西林金黄色葡萄球菌的活性类似于对照药莫西沙星(MIC=1μg/mL),且优于阳性对照药加替沙星(MIC=2μg/mL),而对耐喹诺酮金黄色葡萄球菌的抑制活性则是对照药莫西沙星(MIC=4μg/mL)和加替沙星(MIC=8μg/mL)的 4 或 8 倍。抗炎活性测定结果显示大部分目标化合物表现出良好的抗炎活性,其中化合物5a的活性最好。由药理数据发现,腹腔注射时化合物5a的抑制率为94.01%,远远高于对照药布洛芬(39.56%),而口服给药时5a的抑制率则明显降低;在给药剂量为50 mg.kg-1、给药3 h时活性最好,抑制率为47.32%,略高于布洛芬(44.13%),由此判断化合物5a的口服吸收程度低于对照药布洛芬。
[Abstract]:Since the 21 st century, the problem of bacterial resistance has appeared widely and become more and more serious all over the world. If drug resistance is not curbed, 10 million people will die of drug-resistant infections a year worldwide by 2050, costing as much as $100 trillion a year, according to a survey by the British prime minister's economic adviser. Bacterial resistance is also a serious problem in China. Unfortunately, the development of new antimicrobial agents has not been accompanied by an increase in resistant bacteria. The infection of multidrug resistance and the lack of new antimicrobial agents lead clinicians to reconsider the use of polymyxin as a last resort and polymyxin has not been used in clinical practice for many years because of neurotoxicity and nephrotoxicity. Therefore, it is urgent to find new antimicrobial agents with new structures and new targets. Inflammation is a common pathophysiological phenomenon involving many diseases and the most primitive protective response of the body to harmful stimuli. Inflammation is a serious threat to human health in allergy, autoimmune disease and organ transplant rejection. Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used in the treatment of acute and chronic inflammation, but long-term administration of NSAIDs can lead to some adverse reactions, such as bone injury, gastrointestinal injury, liver injury, and toxic renal injury. Therefore, the development of new and safe anti-inflammatory drugs has certain practical significance. Studies show that most of the compounds with quinoline structure have different biological activities, including anti-microbial, anti-tumor, anti-HIV, anti-inflammatory, anti-malaria, etc. Aminoguanidine and Hydrazone also exhibit good antibacterial and anti-inflammatory activities. In this paper, three series of quinolinone compounds (5a-5mO6a-6hmH7b and 7g) were designed and synthesized by molecular splicing, using 6-hydroxy-3- (4-dihydroquinolinone) as parent, and introducing aminoguanidine and Hydrazone structures. The antibacterial and anti-inflammatory activities of the compounds were determined by in vitro antibacterial test and xylene-induced ear swelling in mice. Of the three series of compounds, only 5a-5m series have better antibacterial activity. The inhibitory effect on Gram-positive bacteria and fungi was better than that on Gram-negative bacteria (MIC = 1-64 渭 g / mL), but on Gram-negative bacteria in addition to 1924 and 2421, the inhibitory effect on Gram-negative bacteria was better than that on Gram-negative bacteria. There was almost no inhibitory effect on the other Gram-negative bacteria. The MIC value of the five series compounds was 1-64 渭 g 路mL ~ (-1) for clinical multidrug resistant bacteria. Among them, the activity of 5 cu 5d and 5k is the best. The MIC values of 1 渭 g/mL.5 series of compounds were similar to those of the control drug moxifloxacin 1 渭 g / mL, and were superior to those of the positive control drug Gatifloxacin 2 渭 g / mL, while the inhibitory activity against quinolone-resistant Staphylococcus aureus was similar to that of the control drug, moxifloxacin 1 渭 g / mL, and its inhibitory activity on quinolone-resistant Staphylococcus aureus was higher than that of the positive control drug Gatifloxacin. It was 4 or 8 times higher than that of the control drug moxifloxacin (MIC4 渭 g / mL) and gatifloxacin (MIC8 渭 g / mL). The results of anti-inflammatory activity test showed that most of the target compounds showed good anti-inflammatory activity, of which the activity of compound 5a was the best. The pharmacological data showed that the inhibition rate of the compound at 5 years after intraperitoneal injection was 94.01, which was much higher than that of the control drug ibuprofen 39.56, but the inhibitory rate of ibuprofen in 5 a was significantly decreased when the dosage was 50 mg 路kg ~ (-1), and the activity was the best at 3 h after the administration of ibuprofen and ibuprofen. The inhibition rate was 47.32, slightly higher than that of ibuprofen 44.13, which indicated that the oral absorption of compound was lower than that of the control drug ibuprofen for 5 years.
【学位授予单位】：延边大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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