本文選題：抗生素 + 水解速率常數　； 參考：《大連理工大學》2016年碩士論文

【摘要】：水解是有機化合物重要的降解途徑之一,水解速率常數是對其進行生態(tài)風險評價的基礎參數,可以通過實驗測定獲得。但是僅憑實驗方法獲取水解數據存在耗時費力、依賴設備和標準品等問題,非常有必要基于實驗數據發(fā)展預測方法。定量結構-活性關系(QSAR)是目前應用較為廣泛的預測技術,能夠基于化合物的分子結構對其理化性質、環(huán)境行為參數和毒理學參數進行預測�？股仡惢衔镌谒h(huán)境中頻繁被檢出,其環(huán)境行為和生態(tài)風險引起廣泛關注,對抗生素水解行為的實驗研究很少,水解預測模型未見報道。依據經濟合作與發(fā)展組織(OECD)提出的QSAR發(fā)展和使用導則,本研究采用多元線性回歸(MLR)算法構建了酯類、酰胺類和抗生素類的水解速率預測模型�？紤]到抗生素類化合物的水解數據較為缺失,本文依照美國環(huán)境保護署于2008年制定的水解實驗導則,測定了七個抗生素的水解速率,并對三個抗生素的水解產物進行分析。主要研究發(fā)現如下：(1)基于從數據庫和文獻中收集的70個堿催化水解數據,構建了酯類模型,模型具有良好的擬合優(yōu)度、穩(wěn)健性和預測能力(R2adj=0.898,Q2LOO=0.851,Q2ext=0.651)。基于從數據庫和文獻中收集的94個水解數據,構建了酰胺類模型,模型具有一定的擬合優(yōu)度、穩(wěn)健性(R2adj=0.681,Q2LOO=0.647)和預測能力。(2)基于20種抗生素的水解速率常數,構建了抗生素的QSAR模型,模型具有良好的擬合能力、穩(wěn)健性(R2adj=0.885,RMSE=0.139,Q2LOO=0.848)。從模型描述符可以看出,分子大小、形狀、對稱性和原子分布等對水解速率影響較大。采用實驗測試的阿莫西林、鹽酸強力霉素的水解數據作為抗生素類預測模型的驗證集,模型預測能力良好。(3)實驗測定了七種抗生素的水解速率常數,其中阿莫西林、鹽酸強力霉素、氯霉素、羅紅霉素易水解；林可霉素、鹽酸環(huán)丙沙星、洛克沙砷不易水解。通過高分辨質譜對阿莫西林、鹽酸強力霉素、青霉素G的水解產物進行了表征,并對可能的水解路徑進行了分析。以阿莫西林為例,水解先是親核試劑(H2O或OH-)對β-內酰胺鍵中C-N鍵進攻,使其斷裂,化合物開環(huán),然后是脫羧基和脫水反應。
[Abstract]:Hydrolysis is one of the most important degradation methods for organic compounds. The hydrolysis rate constant is the basic parameter for ecological risk assessment and can be obtained by experiment. However, it is necessary to develop a prediction method based on experimental data because it is time-consuming and laborious to obtain hydrolytic data only, relying on equipment and standard materials. Quantitative Structure-Activity relationship (QSAR) is a widely used prediction technique, which can predict the physical and chemical properties, environmental behavior parameters and toxicological parameters of compounds based on their molecular structure. Antibiotic compounds are frequently detected in the water environment, their environmental behavior and ecological risks have attracted wide attention. There are few experimental studies on the hydrolysis behavior of antibiotics, and the hydrolysis prediction model has not been reported. Based on the QSAR development and application guidelines proposed by the Organization for Economic Cooperation and Development (OECD), a prediction model of hydrolysis rate of esters, amides and antibiotics was constructed by using the multivariate linear regression (MLR) algorithm. In view of the lack of hydrolytic data of antibiotic compounds, the hydrolysis rate of seven antibiotics was determined according to the hydrolytic experimental guidelines formulated by the United States Environmental Protection Agency in 2008, and the hydrolysis products of three antibiotics were analyzed. The main results are as follows: (1) based on 70 alkali catalytic hydrolysis data collected from database and literature, the ester model is constructed. The model has good fit degree, robustness and predictive ability. Based on 94 hydrolytic data collected from database and literature, an QSAR model of antibiotics was constructed based on hydrolysis rate constants of 20 antibiotics. The model has good fitting ability, and its robustness is 0.885RMSE 0.139Q _ 2LOO _ (0.848). It can be seen from the model descriptors that the molecular size, shape, symmetry and atomic distribution have great influence on the hydrolysis rate. The hydrolysate data of amoxicillin and doxycycline hydrochloride were used as the verification set of antibiotic prediction model. Doxycycline hydrochloride, chloramphenicol, roxithromycin are easy to hydrolyze; lincomycin, ciprofloxacin hydrochloride, roxacin are not easy to hydrolyze. The hydrolysates of amoxicillin, doxycycline hydrochloride and penicillin G were characterized by high resolution mass spectrometry. For example, amoxicillin was hydrolyzed by nucleophilic reagents (H 2O or OH), which attacked the C-N bond in 尾 -lactam bond, broke it, opened the ring of the compound, then decarboxyl group and dehydration reaction.
【學位授予單位】：大連理工大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：X131.2

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