Synthesis, biological activity, and four-dimensional quantitative structure-activity analysis of 2-arylidene...

A series of 18 2-arylidene indan-1,3-dione derivatives was synthesized and tested against Daphnia magna to assess the environmental toxicity of these compounds. Aiming to investigate the toxicity mechanism for this series of compounds, a four-dimensional quantitative structure-activity analysis (4D-QSAR) was performed through the partial least square regression (PLS). The best PLS model was built with two factors and the selected field descriptors, of Coulomb (C) and Lennard-Jones (L) nature, describing 77.43% of variance and presenting the following statistics: r ² = 0.89; SEC = 0.30; Q ² = 0.81; SEV = 0.36. According to the literature, the bioactivity of α,β-unsaturated ketones, a functionality present in the series of compounds under investigation, is related to the conjugated double bond with the carbonyl group. The presence of a positive Coulomb descriptor nearby the carbonyl moieties, obtained as a result of the regression model, indicates that these polar groups are also related to the toxicity on D. magna. From the PLS regression model, the toxicity EC₅₀-48 h values increases with the positive Coulomb descriptor and diminishes with the negative Lennard-Jones descriptors. It could be concluded that the presence of small polar groups in the aromatic ring of the arylidene moiety tends to increase the toxicity, while bulkier apolar substituents lead to a decrease of the toxicity.