本文選題：噻唑 + 線蟲　； 參考：《華東理工大學(xué)》2017年碩士論文

【摘要】：噻唑類化合物以其獨特的含氮、硫雜環(huán)結(jié)構(gòu)和多樣的生物活性,廣泛應(yīng)用于醫(yī)藥、農(nóng)藥、精細(xì)化工等領(lǐng)域。在前期工作中,課題組合成得到了具有一定殺線蟲活性的噻唑類化合物P6及P12。本論文在此結(jié)構(gòu)基礎(chǔ)上進(jìn)行進(jìn)一步的結(jié)構(gòu)衍生,尋找具有更高殺線蟲活性的化合物并進(jìn)一步拓展其他生物活性�；趯衔颬6及P12的結(jié)構(gòu)分析,設(shè)計合成了 29個氨基噻唑類化合物并進(jìn)行了線蟲活性測試。雖然衍生合成的化合物的殺線蟲活性沒有提升,但在活性篩選的過程中發(fā)現(xiàn)其對多粘菌素B具有良好抗菌增效活性,進(jìn)而詳細(xì)研究了其抗菌及抗菌增效活性�；钚詼y試結(jié)果表明,化合物能夠增效多粘菌素B對測試菌株(鮑曼不動桿菌ATCC19606和肺炎克雷伯菌SIPI-KPN-1712)的抗菌活性,且當(dāng)噻唑上的氨基被4-三氟甲基苯基取代時,抗菌增效作用較好。以4-三氟甲基苯亞氨基噻唑類化合物為結(jié)構(gòu)骨架,在噻唑環(huán)4-位引入不同的芳環(huán)及芳雜環(huán),合成了 19個目標(biāo)化合物。抗菌增效活性測試表明,當(dāng)化合物濃度為4 μgml-1時,多數(shù)化合物可使多粘菌素B的最小抑菌濃度(MIC)降低。B6與B16在4 μg ml-1時分別可使多粘菌素B對鮑曼不動桿菌ATCC19606的MIC從1 μgml-1降低至0.125 μgml-1和0.0625 μg ml-1,對肺炎克雷伯菌SIPI-KPN-1712的MIC從32 μg ml-1降低至1 μg ml-1和4 μgml-1。時間-殺菌曲線測試結(jié)果表明,相比于單獨用藥,聯(lián)合用藥能夠減少多粘菌素B的用量并在更短時間內(nèi)達(dá)到持續(xù)殺菌效果。同時,進(jìn)一步研究表明該系列化合物對革蘭氏陽性菌也具有良好的殺菌活性。為了改善其水溶性,基于活性較好的4-三氟甲基苯亞氨基噻唑類化合物,合成了 5個該類化合物的鹽,及一個磷酸酯前藥。測試了化合物的水溶性及抗菌增效活性。結(jié)果發(fā)現(xiàn)目標(biāo)鹽類化合物雖保持了原結(jié)構(gòu)對多粘菌素B抗鮑曼不動桿菌的增效活性,但水溶性并無明顯提升;磷酸酯前藥的水溶性得到了明顯改善,在純水中的飽和溶解度為134.40ppm,在體外實驗中沒有表現(xiàn)出抗菌增效活性,體內(nèi)藥效試驗正在進(jìn)行中。
[Abstract]:Thiazole compounds are widely used in the fields of medicine, pesticides and fine chemicals, due to their unique nitrogen, sulfur heterocyclic structures and various biological activities. In the early work, the thiazole compounds have been combined to obtain a thiazole compound with certain nematide activity P6 and P12.. The compounds with higher nematode activity and further development of other biological activities. Based on the structural analysis of P6 and P12, 29 amino thiazole compounds were designed and synthesized and the nematode activity was tested. Although the nematode activity of the compounds derived from the derivatives did not increase, they were found in the process of screening. Polymyxin B has good antibacterial synergistic activity, and then studies its antibacterial and antibacterial activity in detail. The activity test results show that the compound can increase the antibacterial activity of polymyxin B to test strains (Acinetobacter Bauman ATCC19606 and Klebsiella pneumoniae SIPI-KPN-1712), and the amino group on thiazole is obtained by 4- three fluoromethyl phenyl. 4- three fluoromethyl benzothiazoles were used as the structural skeleton, and different aromatic rings and aromatic heterocyclic rings were introduced at the 4- site of thiazole ring, and 19 target compounds were synthesized. The antibacterial synergistic activity test showed that when the concentration of the compound was 4 u gml-1, the minimum inhibitory concentration of polymyxin B (M IC) reduced.B6 and B16 at 4 mu g ml-1, respectively, to reduce the MIC from 1 gml-1 to 0.125 mu gml-1 and 0.0625 mu g ml-1, respectively. The results of the reduction of Klebsiella pneumoniae from 32 Mu to 1 mu and 4 micron time - bactericidal curve test showed that compared with the individual drug use, The combined drug can reduce the dosage of polymyxin B and achieve sustained bactericidal effect in a shorter time. At the same time, further studies have shown that the series of compounds also have good bactericidal activity for Gram-positive bacteria. In order to improve their water solubility, 5 kinds of compounds have been synthesized based on the better activity of three fluoromethyl benzothiazoles. The water solubility and antibacterial synergistic activity of the compound were tested. The results showed that the water solubility of the target salt compound had not increased significantly, although the target salt compound kept the synergistic activity of the original structure against the polymyxin B against Acinetobacter Bauman, and the water solubility of the phosphate ester was obviously improved and satiated in pure water. And solubility of 134.40ppm, in vitro experiments showed no antibacterial synergistic effect, in vivo pharmacodynamic test is in progress.
【學(xué)位授予單位】：華東理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：TQ252.5

【參考文獻(xiàn)】

相關(guān)期刊論文 前5條

1 姬勛;王江;張磊;趙臨襄;蔣華良;柳紅;;磷酸酯前藥在藥物研究中的應(yīng)用[J];藥學(xué)學(xué)報;2013年05期

2 陳川;肖新榮;梁俊;夏岳韜;賈小鵬;陶源;;3-甲基-5-苯基-2-(3-氟苯基)嗎啉鹽酸鹽合成及其抗實驗性抑郁活性[J];應(yīng)用化工;2012年02期

3 劉群英;趙建戟;;介紹三種噻唑類農(nóng)藥[J];西北園藝(果樹);2011年04期

4 黃光;楊吉春;李慧超;張靜;劉長令;;具有農(nóng)藥活性的噻唑類化合物的研究進(jìn)展[J];農(nóng)藥;2011年02期

5 王謙;孫素馨;;抗菌增效劑應(yīng)用進(jìn)展[J];臨床醫(yī)藥實踐雜志;2007年S1期

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本文編號：2020729