Yang Chuanxi, Wang Xiaoning, Zhao Xinyan, Wu Yongkun, Lin Jingyan, Zhao Yuhan, Xu Yiyong, Sun Kaipeng, Zhang Chao, Wan Ziheng, Zhao Weihua, Xiao Yihua, Sun Haofen, Chen Dong, Dong Wenping, Wang Tieyu, Wang Weiliang
School of Environmental and Municipal Engineering, Qingdao University of Technology, Qingdao 266520, China.
Business School, Qingdao University of Technology, Qingdao 266520, China.
Environ Health (Wash). 2024 Aug 22;2(12):886-901. doi: 10.1021/envhealth.4c00095. eCollection 2024 Dec 20.
To clarify the effect of the fluorine atom and piperazine ring on norfloxacin (NOR), NOR degradation products (NOR-DPs, P1-P8) were generated via UV combined with hydrogen peroxide (UV/HO) technology. NOR degradation did not significantly affect cytotoxicity of NOR against BV2, A549, HepG2, and Vero E6 cells. Compared with that of NOR, mutagenicity and median lethal concentration of P1-P8 in fathead minnow were increased, and bioaccumulation factor and oral median lethal dose of P1-P8 in rats were decreased. Molecular docking was used to evaluate the inhibitory effect of DNA gyrase A (gyrA) on NOR-DPs to determine the molecular-level mechanism and establish the structure-activity relationship. Results indicated that the most common amino acid residues were Ile13, Ser27, Val28, Gly31, Asp36, Arg46, Arg47, Asp157, and Gly340; hydrogen bonds and hydrophobic interactions played key roles in the inhibitory effect. Binding area (BA) decreased from 350.80 Å (NOR) to 346.21 Å (P1), and the absolute value of binding energy (|BE|) changed from 2.53 kcal/mol (NOR) to 2.54 kcal/mol (P1), indicating that the fluorine atom mainly affects BA. The piperazine ring clearly influenced BA and |BE|. "Yang ChuanXi Rules" were used to explain effects of molecular weight (MW), BA, |BE|, and sum of η + η (η: normalization of BA, η: normalization of |BE|) and predict biotoxicity of NOR-DPs based on half-maximum inhibitory concentration (IC), half-minimal inhibitory concentration (MIC), and half-minimal bactericidal concentration (MBC) values.
为阐明氟原子和哌嗪环对诺氟沙星（NOR）的影响，通过紫外线联合过氧化氢（UV/H₂O₂）技术生成了NOR降解产物（NOR-DPs，P1-P8）。NOR降解对NOR对BV2、A549、HepG2和Vero E6细胞的细胞毒性没有显著影响。与NOR相比，P1-P8在黑头呆鱼中的致突变性和半数致死浓度增加，而P1-P8在大鼠中的生物累积因子和经口半数致死剂量降低。采用分子对接评估DNA促旋酶A（gyrA）对NOR-DPs的抑制作用，以确定分子水平机制并建立构效关系。结果表明，最常见的氨基酸残基为Ile13、Ser27、Val28、Gly31、Asp36、Arg46、Arg47、Asp157和Gly340；氢键和疏水相互作用在抑制作用中起关键作用。结合面积（BA）从350.80 Å（NOR）降至346.21 Å（P1），结合能绝对值（|BE|）从2.53 kcal/mol（NOR）变为2.54 kcal/mol（P1），表明氟原子主要影响BA。哌嗪环对BA和|BE|有明显影响。利用“杨传玺规则”解释分子量（MW）、BA、|BE|以及η + η之和（η：BA归一化，η：|BE|归一化）的影响，并基于半数最大抑制浓度（IC）、半数最小抑制浓度（MIC）和半数最小杀菌浓度（MBC）值预测NOR-DPs的生物毒性。
