Modification of Hexachlorobenzene to Molecules with Lower Long-Range Transport Potentials Using 3D-QSAR Models with a Full Factor Experimental Design

Abstract

In this study, the hexachlorobenzene molecule was modified by three-dimensional quantitative structure-activity relationship (3D-QSAR) models and a full factor experimental design to obtain new hexachlorobenzene molecules with low migration ability. The 3D-QSAR models (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) were constructed by SYBLY-X 2.0 software, using experimental data of octanol-air partition coefficients (K_OA) for 12 chlorobenzenes (CBs) congeners as the dependent variable, and the structural parameters of CBs as independent variables, respectively. A target molecule (hexachlorobenzene; HCB: its long-distance migration capability leads to pollution of the marine environment in Antarctic and Arctic) was modified using the 3D-QSAR contour maps associated with resolution V of the 2^10-3 full-factorial experimental design method, and 11 modified HCB molecules were produced with a single chlorine atom (-Cl₂) and three chlorine atoms (-Cl₁, -Cl₃, and -Cl₅) replaced with electropositive groups (-COOH, -CN, -CF₃, -COF, -NO₂, -F, -CHF₂, -ONO₂, and -SiF₃) to increase the logK_OA. The new molecules had essentially similar biological enrichment functions and toxicities as HCB but were found to be more easily degraded. A 2D-QSAR model and molecular docking technology indicated that both dipole moments and highest occupied orbital energies of the substituents markedly affected migration and degradation of the new molecules. The abilities of the compounds to undergo long distance migration were assessed. The modified HCB molecules (i.e. 2-CN-HCB, 2-CF₃-HCB, 1-F-3-COOH-5-NO₂-HCB, 1-NO₂-3-CN-5-CHF₂-HCB and 1-CN-3-F-5-NO₂-HCB) moved from a long-range transport potential of the modified molecules to a relatively low mobility class, and the transport potentials of the remaining modified HCB molecules (i.e. 2-COOH-HCB, 2-COF-HCB, 1-COF-3-ONO₂-5-NO2-HCB, 1-F-3-CN-5-SiF₃-HCB, 1-F-3-COOH-5-SiF₃-HCB and 1-CN-3-SiF₃-5-ONO₂-HCB) also significantly decreased. These results provide a basic theoretical basis for designing environmentally benign molecules based on HCB.

Keywords: 3D-QSAR; Full-factorial experimental design; Hexachlorobenzene; Marine environment; Migration ability; Molecule modification; Octanol–air partition coefficients.