Molecular Modification And Research On Mechanism Of Fluoroquinolones With More Environmental Friendliness

Fluoroquinolones(FQs)which detected in sewage,manure and sewage sludge are widely used as antibiotics in the health care and livestock aquaculture industries,they induce the production of bacterial resistance in soil environment microorganisms,animals and humans,and interfere with the normal physiological functions of animals and plants,affecting ecosystem balance and human health through the food chain.As emerging contaminants,they have been attracted wide attention.High concentration FQs in medical wastewater,pharmaceutical wastewater and aquaculture wastewater forms high-intensity selective pressure on microbial communities in biochemical units of sewage treatment facilities,resulting in low removal efficiency.The purpose of this study is to control and mitigate the adverse environmental effects of FQs from the source based on the relationship between molecular structure and material properties of FQs,and provides theoretical reference for the prevention and control of emerging contaminants,especially the environmental pollution of pharmaceutical compounds.Firstly,the molecular structure modification information which is beneficial to the improvement of material properties is revealed by constructing a quantitative structure-activity relationship model of functional properties(bacterial genotoxicity)and environmental properties(photolysis,bioaccumulation),which guide the design of FQs derivatives with improved functional properties and environmental friendliness.The quantum chemical calculation method was used to infer the path and mechanism of FQs photosensitization reaction.The interaction between FQs and its derivatives and DNA and its topoisomerase was investigated by molecular docking method.The difference and mechanism of bioaccumulation and bacterial genotoxicity were revealed which verified the effect of the modification method at the molecular biology leve.In order to analyze potential environmental risks,the genotoxicity changes of degradation products in vivo metabolism,photolysis,microbial degradation and chlorination disinfection process of FQs derivatives were investigated.The main research contents and results are as follows:1?Based on experimental data for the Photolysis half-life(logt1/2)of FQs molecules,two types of three-dimensional QSAR(3D-QSAR)models,comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)were established,the contour maps of two models showed molecular modification indication information which is favorable for the photolysis half-life t1/2 shortening.A modified group was introduced at the C-13 position(template molecule:ciprofloxacin CIP)of the piperazine ring to obtain 9 CIP derivatives with improved photolysis.It was found that the functional properties were not reduced while the photolysis characteristics were improved with the prediction of genotoxic 3D-QSAR model.The energy barrier and reaction heat of CIP photosensitization reaction pathway were calculated by quantum chemistry methods.It was found that aromatic ring hydroxylation was the main type of reaction,oxidative decarboxylation reaction was the most difficult to occur,and piperazine ring rupture was the most likely.When the photolysis half-life t1/2 is shortened,the energy barrier required for photolysis of the piperazine ring is also reduced.It was found that CIP and its derivatives produced products with improved biodegradability after photolysis by investigating the binding ability between molecules with white rot fungi laccase,and the products obtained by piperazine ring cleavage were the most significant.2?Based on experimental data for the octanol-water partition coefficient(Kow)of FQs molecules,comparative molecular similarity indices analysis(CoMSIA)was established,the contour maps of the CoMSIA model showed molecular modification indication information which is favorable for the bioaccumulation decreasing.23 NAD derivatives(template molecule:Napofloxacin NAD)were obtained by monosubstituted and double substituted at C-3 and C-18,respectively.QSAR and molecular docking methods were used to predict and evaluate bacterial genotoxicity,photolysis and the binding ability between molecules and bacterial DNA topoisomerase,selecting 13 derivatives with low bioaccumulation,high genotoxicity and photodegradability.Molecular docking method was used to investigate the interaction between NAD and its derivatives and bacterial DNA topoisomerase molecules.It was concluded that the difference in bioconcentration was related to the hydrophobic properties of the involved amino acid residues in the enzyme protein at the site of action,and the interaction between the hydrophilic group and the surrounding free water molecules in the derivatives.3?The HQSAR model of FQs molecular topology information and genotoxicity(functional characteristics)of Salmonella typhimurium(Gram-negative bacteria)was constructed by PLS method.The molecular modification indication information which is beneficial to genotoxicity enhancement was obtained by activity contribution map analysis,and then 35 FQs derivatives were designed by introducing a modification group at the C-7 position to obtain.QSAR and molecular docking methods were used to predict and evaluate photolysis,bioaccumulation and its ability to bind to DNA-topoisomerase.Finally,four kinds of derivatives with significantly improved bactericidal effect and environmental friendliness were screened out.The molecular docking method was used to investigate the interaction between Ammofloxacin(AMI)and its derivatives and topoisomerase IV-DNA complexes.It was found that arginine ARG,asparagine ASN,aspartate ASP and leucine LEU were the main amino acid species,and the hydrophilicity has an important influence on the combination.The electrostatic action is stronger than the van der Waals force.The increase in the use of amino acids invovled electrostatic action is conducive to the enhancement of the binding ability.4?2D-QASR and factor analysis methods were used to investigate the effects of molecular parameters(including electronic parameters,physical and chemical parameters,spectral parameters and geometric parameters)on the genotoxicity of four types FQs(32).Boiling Point(BP),Critical Temp(CT),Energy Gap(EG)parameters,and steric parameter(MR),molecular weight(Molecular Weight,Mol Wt)Infrared CO bond vibration frequency(IR-(CO)svf)parameters play a major role,which can provide indication information for molecular modification of FQs bacterial genotoxicity.5?The transformation pathways and products of 6 FQs derivatives in vivo metabolism,natural photolysis,microbial degradation and chlorination process were inferred.The HQSAR model was used to predict and analyze the changes in the genotoxicity of the transformed products compared with the parent derivatives,which found some of the other three degradation processes have potential environmental risks in addition to the general decrease in chlorination products.