Environmental Quantitative Structure-activity Relationship Studies On 2-hydroxy-1,4-naphthoquinones As Inhibitors Of Psii And Triazole Fungicides

Environmental QSAR studies are the important means to evaluate the environmental effects caused by more and more chemicals existing in the environment. In the researches of organic chemistry about pollutants and ecotoxicology, environmental QSAR studies play two roles. One is to analyse the mechanism of environmental effects to offer the theoretical guidance of pollutants'environmental risk's decreasing. The other is to predict, evaluate and screen of environmental behavior and eco-toxicity of unknown compounds. So, the ideal QSAR models not only have high predictive ability, but also can explain the mechanisms of environmental effects reasonably.In this paper, 2-hrdroxy-3-alkyl-1,4-naphthoquinones as inhibitors to PSII and triazole fungicides were regarded as research objects. The inhibitory mechanism and active sites of naphthoquinones to PSII, the toxic mechanism and active sites of triazoles to aquatic organisms and the environmental effects induced by triazoles were studied by using QSAR technique. The objective of the paper is to establish the environmental QSAR pattern to analyse and evaluate the environmental risk and effect of pesticides.2D-QSAR and HQSAR methods were used to study the PSII inhibitory activity of 23 2-hydroxy-3-alkyl-1,4-naphthoquinone derivatives. Based on it, 3D-QSAR including CoMFA and CoMSIA were employed to study the inhibitory activity. The QSAR models having the high fitting degrees and predictive abilities could interpret the PSII inhibitory mechanism reasonably. Compared with 2D-QSAR, HQSAR and 3D-QSAR models had the higher predictive abilities. The results showed that the inhibitory process might include two steps. Firstly, the inhibitors migrated from water to biological phase, arrived at the target through the membrane. Secondly, the inhibitors were possible to combine with the target via 3-alkyl's hydrophobic interaction with the non-polar groups of D1 and acyl-oxygen's H-bond interaction with the amino acid residues of D1. Thus, naphthoquinones competed with QB to block the electron's transfer process of plant photosynthesis. 3D-QSAR results showed that the shape, size and hydrophobicity of 3-alkyl could affect the ability of compound through the membrane, and the 4-alcyl-oxygen could combine with D1 using H-bond easily. 3-alkyl and 4-carbonyl were probably the active sites of inhibitory reaction.BTo analyse the aquatic ecological toxicity of 17 triazole fungicides and provide the data for QSAR study, the acute immobilization test for the crustacean (Daphnia magna) at 48h (expressed as EC₅₀(48h)) and acute toxicity for the zebrafish (Danio rerio) at 96h (expressed as LC₅₀(96h)) were determined by static system. At the same time, the infections of traizoles to the safety of aquatic ecology were basically assessed.2D-QSAR and 3D-QSAR methods including CoMFA and CoMSIA were used to study the toxicities of triazoles to D. magna and D. rerio. The QSAR models having the high fitting degrees and predictive abilities could interpret the mechanism of toxicity to D. magna and D. rerio reasonably. Compared with 2D-QSAR, 3D-QSAR models had the higher predictive abilities. 2D-QSAR results showed that the pollutants firstly might accumulate in organisms through the membrane. The process could be controlled by the hydrophobic parameters (ClogP) and molecular topological indices (ShpC and Dia). The pollutants might have the anaesthetic effect. Then, the pollutants could change the electron or nucleophilically displace with the biological macromolecules which could be affected by the electrical parameters. The pollutants might also have the reactive toxicity, higher than the anaesthetic toxicity. Moreover, 3D-QSAR studies indicated that the nitrogen atom in triazole ring might provide the lone pair electrons to form coordinate bond with the iron atom in the active center of CYP450 porphyrin ring. Phenyl and alkyl groups could form the hydrophobic interaction with the aromatic receptor of CYP450 and block the normal physiological function of CYP450. Therefore, triazole fungicides are toxic to D. magna and D. rerio. Comparing the results of 2D-QSAR and 3D-QSAR studies, one phenomenon that the toxic mechanisms of triazoles to D. magna were similar to D. rerio was found. Additionally, triazole ring, para positions of benzene ring and the substituted group linked with silicon atom were probably the active sites of toxic reaction.In order to validate the conjecture about the mechanism of triazoles on D. rerio in 3D-QSAR study and forecast the infection and potential environmental effects of triazoles to aquatic organisms on molecular level. The activities of SOD and CAT in the livers of zebrafish exposed to the various concentrations of paclobutrazole were measured, paclobutrazole as an example. The results indicated that the responses of SOD and CAT's activities to triazoles were likely to be because of the interaction between CYP450 and triazoles which resulted in the interruption of natural cyclic catalytic reactions and then, the ROS increasing and the activities of SOD and CAT affected.