本文選題：喹啉酮 + 氨基胍��； 參考：《延邊大學(xué)》2017年碩士論文

【摘要】：21世紀(jì)以來(lái),細(xì)菌耐藥性問題在全球范圍內(nèi)都廣泛出現(xiàn),并且日益嚴(yán)重。根據(jù)英國(guó)首相經(jīng)濟(jì)學(xué)顧問的調(diào)查報(bào)告,如果細(xì)菌耐藥性不加遏制,到2050年全球每年將有1000萬(wàn)人死于耐藥菌感染,每年的經(jīng)濟(jì)損失將高達(dá)100萬(wàn)億美元。在中國(guó),細(xì)菌耐藥問題同樣嚴(yán)重。遺憾的是,新型抗菌藥物的研發(fā)并沒有伴隨著耐藥性細(xì)菌的增加而增加。多藥耐藥的感染加上缺乏新的抗菌藥物,導(dǎo)致臨床醫(yī)生開始重新考慮使用多黏菌素作為最后的治療手段,而多黏菌素由于存在神經(jīng)毒性和腎毒性,已經(jīng)多年未在臨床中使用。因此,尋找具有新結(jié)構(gòu)和新靶點(diǎn)的新型抗菌藥物已迫在眉睫。炎癥是一種常見的病理生理現(xiàn)象,涉及許多疾病,是身體對(duì)有害刺激最原始的保護(hù)性反應(yīng)。炎癥在過敏反應(yīng)、自身免疫性疾病和器官移植排斥等方面嚴(yán)重威脅著人類的健康。非甾體抗炎藥在治療急性和慢性炎癥方面的應(yīng)用已非常普遍,但是長(zhǎng)期服用會(huì)產(chǎn)生一些不良反應(yīng),如骨組織損傷、胃腸道損傷、肝臟損傷、中毒性腎損傷。因此開發(fā)新型安全的抗炎藥物具有一定的實(shí)際意義。研究顯示,多數(shù)含有喹啉結(jié)構(gòu)的化合物具有不同的生物活性,包括抗微生物、抗腫瘤、抗HIV、抗炎、抗瘧疾等;氨基胍與腙類化合物也表現(xiàn)出良好的抗菌與抗炎活性。本文作者通過分子拼接的方法,以6-羥基-3,4-二氫喹啉酮為母體,引入氨基胍與腙類結(jié)構(gòu),設(shè)計(jì)合成了三個(gè)系列5a-5m,6a-6h,7a、7b和7g共24個(gè)喹啉酮類化合物,并通過體外抗菌實(shí)驗(yàn)和二甲苯誘導(dǎo)小鼠耳腫脹實(shí)驗(yàn)測(cè)定化合物的抗菌與抗炎活性。三個(gè)系列化合物中,只有5a-5m系列化合物有較好的抗菌活性,且對(duì)革蘭氏陽(yáng)性菌和真菌的抑制作用優(yōu)于革蘭氏陰性菌,MIC值為1-64 μg/mL;而對(duì)革蘭氏陰性菌除了對(duì)1924和2421有較好的抗菌抑制作用外,對(duì)其余革蘭氏陰性菌幾乎都沒有抑制效果,5系列化合物對(duì)臨床多重耐藥菌也有較強(qiáng)的抗菌效果,MIC值為1-64μg/mL。其中,化合物5c、5d和5k的活性最好,其MIC值均達(dá)到1μg/mL。5系列化合物對(duì)耐甲氧西林金黃色葡萄球菌的活性類似于對(duì)照藥莫西沙星(MIC=1μg/mL),且優(yōu)于陽(yáng)性對(duì)照藥加替沙星(MIC=2μg/mL),而對(duì)耐喹諾酮金黃色葡萄球菌的抑制活性則是對(duì)照藥莫西沙星(MIC=4μg/mL)和加替沙星(MIC=8μg/mL)的 4 或 8 倍�？寡谆钚詼y(cè)定結(jié)果顯示大部分目標(biāo)化合物表現(xiàn)出良好的抗炎活性,其中化合物5a的活性最好。由藥理數(shù)據(jù)發(fā)現(xiàn),腹腔注射時(shí)化合物5a的抑制率為94.01%,遠(yuǎn)遠(yuǎn)高于對(duì)照藥布洛芬(39.56%),而口服給藥時(shí)5a的抑制率則明顯降低;在給藥劑量為50 mg.kg-1、給藥3 h時(shí)活性最好,抑制率為47.32%,略高于布洛芬(44.13%),由此判斷化合物5a的口服吸收程度低于對(duì)照藥布洛芬。
[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.
【學(xué)位授予單位】：延邊大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R914;R96

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