A Number Of Organic Compounds In Quantitative Structure - Property / Activity Relationships And Joint Toxicity Studies

The research presented in the thesis focus on two areas. One is the quantitative structure-property/activity relationship; the other is the mixture toxicity. To avoid the costly and time-consuming environmental fate testing, the quantitative structure-property/activity relationships have been effectively used to screen large classes of chemicals. QSPR/QSAR represent predictive tools that can be used for a preliminary assessment of chemical hazard when experimental data are not available. The choice of the descriptors used, and thus the extent to which they encode the structural features of the molecules, represents one of the more crucial parts of QSPR/QSAR study. Impact of chemicals and hazardous substances on the environment often occurs as the mixtures rather than the single component. These chemical mixtures may result in different interactions on organisms rather than what would be observed from the individual chemical alone. Due to the above recognition, the joint toxic effects of multiple chemicals have been recognized as an important consideration. Aromatic sulfur-containing esters, used extensively as intermediates in the manufacture of pesticides, and also in petrochemical and metallurgical industries, are introduced into the environment. Their environmental behaviors and ecological effects should be investigated. The TLSER and atomic charge methods were applied to model the partition properties (water solubility and octanol/water partition coefficients). The obtained models can reveal the partitioning mechanics for the structural dependence of compound properties. On the basis of physicochemical parameters (KOW and SW), the TLSER descriptors, the atomic charge model descriptors and the E-state indices, QSAR were calculated for the inhibition of bioluminescence to Photobacterium phosphoreum and the immobilization of Daphnia magna, respectively. Using the models, the acute toxicity related parameters could be related to fundamental descriptors of the molecule. For the partition properties (KOW) of 47 various organic compounds, the suitable model was founded with the solvation free energy (△GS). The increasing solubility and the decreasing toxicity of α-substituted phenylsulfonyl acetates by β-cyclodextrin (β-CD) were investigated. For the stability of the inclusion complex and the decreasing toxicity, the models were founded and revealed the related mechanisms. The mixture toxicity of the substituted phenylsulfonyl acetates was determined in P. phosphoreum test. Using the toxicity indicators, the joint toxic effect is quantified and analyzed. The application of QSAR model in predicting joint toxicity of mixtures of the chemicals is presented. The detailed results are concluded as follows, 1. The regression model for octanol/water partition coefficients (KOW), was founded with only two molecular descriptors available through quantum chemical calculations: the solvation free energy (△GS) and the solvent-accessible surface area (SASA). For the properties of 47 organic compounds from 17 types, the model gives a correction coefficient (adjusted for degrees of freedom) of 0.957 and a standard deviation of 0.277 log unit. It is a suitable way to predict the partition properties that are related to solute-solvent interactions in the water phase. 2. Water solubility and octanol/water partition coefficients of 20 α-substituted phenylsulfonyl acetates were determined. The TLSER and atomic charge methods were applied to model the properties. For TLSER, the introduction of structural indicator variable I into the model largely improves the predictive power. For the atomic charge method, the utilized molecular descriptors are molecular surface (S), weight (MW), ovality (O), charge densities on carboxyl, nitro group, nitrogen and sulfur atoms of the molecule. The correction coefficients r2adj (adjusted for degrees of freedom) of 0.971 and 0.984, and the standard errors of 0.159 and 0.132 for lgSW and lgKOW, reveal that the models are successful. 3. Based on quantum chemical calculations, atomic charge approach was applied to model the partition properties of 96 aromatic sulfur-containing esters, including phenylthio, phenylsulfinyl and phenylsulfonyl esters. The molecular descriptors are molecular surface (S), weight (MW), net charge on carboxyl group (QOC), nitrogen atom (QN), and the most negative atomic net charge (q-) of the solute molecule. The correction coefficients r2adj (adjusted for degrees of freedom) of 0.938 and the standard error of 0.223, reveal that it is accurate and reliable for the model to predict the partition properties of the kind of compounds. 4. The acute toxicity (15min-EC50) of 20 α-substituted phenylsulfonyl acetates was measured using the Microtox test with P. phosphoreum. On the basis of TLSER, QSAR were calculated for the inhibition of bioluminescence. With the parameters of molecular volume (Vmc), dipolarity/polarizability (π*) and the covalent contribution to Lewis basicity(εb), a squared correlation coefficient (r2adj) of 0.868 and a standard deviation (SD) of 0.094 for lg EC50 were obtained. Introducing a structural indicator variable (I), the regressive quality was improved (a correlation coefficients of 0.948 and a standard error of 0.059); the descriptors of Vmc, π* and the electrostatic basicity contribution (q-) were significant. The -SO2-and -CO2-groups are active centers of these compounds. Thestrong hydrogen-bonding effects between the compound active centers and FMNH2 play an important role on the higher toxicity of these chemicals. 5. The acute toxicity (48h?EC50, μM) of 20 α?substituted phenylsulfonyl acetates was measured using Daphnia magna with a static method. On the basis of physicochemical parameters (octanol/water partition coefficient lgKOW and aqueous solubility lgSW), the TLSER and atomic charge model descriptors, QSAR were calculated for the immobilization of D. magna. For the models with the parameters lgKOW and lgSW, the low squared correlation coefficients indicate that hydrophobicity plays a dominant role on the toxicity and hydrophobicity is not the only factor that influences the activity of the compounds. For the TLSER model and the atomic charge model, the great squared correlation coefficients suggest that the models have good predictive capability. The higher activity of the compounds can be explained with the disruption of van der Waals interactions between lipid and/or protein compounds within the membrane and the possibility of the compounds to form hydrogen bonds with the receptor molecules. The models may more completely illustrate the toxicity mechanism. 6. Using the electrotopological state (E-state) indices consisted of atom E-state, atom-type E-state and grouped E-state indices, two four-variable models were founded for the acute toxicity to P. phosphoreum and D. magna, respectively. The models gave good statistics: r2adj is 0.944 and 0.930, SD is 0.062 and 0.064. The models suggest that hydrophobicity plays an important role on the toxicity, the electrostatic interactions including polarity effects and hydrogen-bonding effects between the compound and receptor molecules have significant influence on the activity, and the -SO2-and -CO2-groups are active centers of these compounds. 7. The solubilization and the decreasing toxicity of 10 α?substituted phenylsulfonyl acetates by β-CD were investigated. The apparent solubility of the compounds was significantly increased in β-CD solutions. The chemicals form 1:1 complexes with β-CD. With the compound partition property (lgKOW) and the E-state indices, the complexation constants (lgKS) were analyzed. The partitioning mechanism is a valid approach for interpreting the solubilization activity of β-CD. The effect on the complexation seems to be a combination of the release of "high energy"water in β-CD cavity, van der Waals interaction and hydrogen bonding between the guest and β-CD. β-CD reduces the toxicity of the chemicals to P. phosphoreum. The decreasing extent of toxicity has a positive correlation with the complexation constant. It is clear that the inclusion forming influences the toxicity of these compounds in P. phosphoreum test.8. In P. phosphoreum test, the joint toxicity (15min-EC50, μmol/L) from several different binary and multi-component, uniform and non-uniform mixture were determined. Using the toxicity indicators such as TU, AI and MTI, the joint toxic effect is quantified and analyzed. The joint toxic effects of the chemicals can be considered simply additive. A QSAR model from single chemical toxicity assays was used to predict concentrations of components in mixtures that would jointly cause 50% inhibition of bioluminesence. The predictions made from the QSAR model agreed well with the experimental data with r2adj=0.983 at p=0.001 for a total of 417 data points.