低光降解性氟喹诺酮类抗生素的分子设计及光解路径推断

Molecular Design of Lower Photodegradation Fluoroquinolone Antibiotics and Their Photolysis Paths Inference

以已知光降解半衰期(t1/2)的12种氟喹诺酮(FQs)同系物按摩尔比4∶1选择训练集和测试集(随机组合),釆用Sybyl-X 2. 0软件QSAR模块中结合比较分子力场分析(Co MFA)方法和比较分子相似性指数分析(Co MSIA)方法进行三维定量构效关系(3D-QSAR)研究,建立以FQs分子结构参数为自变量,lgt1/2为因变量的3D-QSAR模型,并预测剩余14种FQs分子的t1/2.结果表明,任意组合所构建的Co MFA和Co MSIA模型交叉验证相关系数q2在0. 564～0. 655区间内(> 0. 5),非交叉验证相关系数r2在0. 996～1. 000区间内(>0. 9),表明所构建模型稳定性较强且预测能力良好;对剩余14种FQs分子的t1/2预测发现,第四类FQs的t1/2普遍高于第三类FQs;选取环丙沙星(CIP)为目标分子,QSAR三维等势图分析其C-13位置引入体积较小的基团有利于降低目标分子的t1/2值,据此设计出9种t1/2值显著降低的新型CIP分子,其中引入·OH基团的新型分子t1/2下降幅度最为显著(27. 2%);对CIP分子以及新型CIP分子可能发生的光降解路径进行推断发现,CIP光降解过程中发生芳香环羟基化的路径所需能垒最小,推断为FQs类抗生素降解过程中的主要反应类型,而氧化脱羧反应能垒最大,发生哌嗪环断裂的路径最多,而新型CIP分子光解过程中发生芳香环羟基化、氧化脱羧及羟基化脱氟3种反应的能垒较原CIP分子变化不大,仅哌嗪环断裂所需要能垒明显小于CIP分子需要的能垒;新型CIP分子及其光解产物的生物降解性评价发现,新型CIP分子不仅光解活性提高,其生物降解性同时提高0. 26%～59. 71%,且其光解产物的生物降解性也显著上升(12. 03%～34. 38%),即CIP分子以及新型CIP分子可通过光降解最终生成生物降解性显著提高的物质,从而达到进一步控制FQs环境行为的目的.

Dividing the obtained data of photodegradation half-life(t1/2)for 12 fluoroquinolones(FQs)into the training set and test set in a radio of 4∶1(random combination),comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)were used to establish 3D-QSAR models to predict the lgt1/2 values of the remaining 14 FQs,with the structural parameters as independent variables and the lgt1/2 values as the dependent variables through the Sybyl-x software.The results showed that the cross-validation correlation coefficients(q^2)for CoMFA and CoMSIA models constructed by random combination were 0.564-0.655(>0.5)and the non-cross-validated correlation coefficients(r^2)were 0.996-1.000(>0.9),indicating that the models were robust and predictive.The prediction of the photolysis t1/2 found that the fourth type of FQs generally had a higher t1/2 value than the third type of FQs.Taking cipro-floxacin(CIP)as the target molecule,introducing the smaller groups at the selected C13 position of CIP helped to design 9 modified CIP molecules with t1/2 values significantly decreased,and the t1/2 value of the modified molecule with the introduction of OH groups reduced most(27.2%).The photodegradation paths inference of CIP molecules and modified molecules indicated that the minimum energy barrier was required for the path of aromatic ring hydroxylation during CIP photodegradation,and the oxidative decarboxylation reac-tion had the largest energy barrier and the most paths of piperazine ring fracture.For the modified CIP mole-cules,the energy barriers of three reactions,aromatic ring hydroxylation,oxidative decarboxylation,and hydroxylation defluorination remained basically unchanged but the energy barrier required for the piperazine ring fracture significantly reduced.Evaluation of the biodegradability of modified CIP molecules and their pho-tolysis products revealed that not only the photolytic activity of modified CIP molecules increased,but also the biodegradability increased by 0.26%to 59.71%,and the biodegradability of the photolysis products also in-creased significantly(12.03%-34.38%).It indicated that CIP and modified CIP molecules can eventually generate products with significantly improved biodegradability through photodegradation in favor to further con-trol the environmental behaviors of FQs.