Molecular design of 1,3,5,7-TetraCN derivatives with reduced bioconcentration using 3D-QSAR modeling, full factorial...

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were established for polychlorinated naphthalenes (PCNs) using the logarithms of experimental bioconcentration factors of 10 PCNs in fish as the dependent variable and their molecular structures as the independent variable. The models were used to design PCN derivatives with lower bioconcentration than the parent compounds. The contour maps from the 3D-QSAR models were used to evaluate sites and different substituents for monosubstitution. A full factorial experiment based on the target molecule (1,3,5,7-tetraCN, CN-42) was used to evaluate sites for disubstitution. The established 3D-QSAR models had good predictive abilities for the remaining 65 PCN congeners. Comparative molecular field analysis and comparative molecular similarity indices analysis models showed that PCN bioconcentration was dominated by the electrostatic field. Taking CN-42 as a template, 15 new monosubstituted compounds and 19 new disubstituted compounds with lower bioconcentration than CN-42 were designed using the 3D-QSAR model and full factorial design, respectively. Furthermore, the persistent organic pollutant properties and the practicability of these compounds were evaluated using Gaussian 09. The new compounds were less toxic than CN-42 but showed similar migration, stability, insulation, and flame retardancy. Molecular docking was used to screen for CN-42 derivatives that showed lower bioconcentration than CN-42 in specific tissues.