Synthesis And Bioactivities Of N-phenylpyrazole Derivatives Containing A Sulfur Ether Moiety

The sulfur ether moiety is an active pharmacophore molecule,which exhibited diverse physicochemical properties by non–covalent bonds interactions with bio–macromolecules.Therefore,thioether derivatives containing heterocyclic moiety are known for their interesting insecticidal bioactivities and attracting considerable attention as neuroactive insecticides.Fipronil is the second generation phenylpyrazole insecticides,which acts on the?–aminobutyric acid?GABA?receptor in the central nervous system of insects,and has high insecticidal activity for insect pests such as Lepidoptera,Hemiptera and Coleoptera,as well as a variety of hygienic insect pest.Meanwhile,after decades of intensive use,many target pests have developed higher resistance to fipronil,and owing in part to its high toxicity to beneficial organisms,fipronil was greatly limited to be used as a pesticide in China since 2009.Due to the excellent bioactivity of fipronil,it has attracted more interest as lead in the discovery of agrochemicals,which possess execllent insecticidal activity,low mannalian toxicity and no prone to resist.To reduce resistance and toxicological risk,this paper firstly reports a series of fipronil derivatives containing an arylalkyl thioether moiety at 4-position of the pyrazole ring by different length of the spacer arm.The bioactivity of target compounds to adult of Musca domestica and 3th instar larvae of Spodoptera litura and Plutella xylostella were determined by residual film method,feed mixing method and leaf–dip method respectively.Structure–activity relationship?SAR?studies resulted in compounds 6d and 7d with the most potent insecticidal activity against Musca domestica L.among the series containing various substituted benzene substituents(LC₅₀=13.70-25.47?g/mL).According to the principle of bioelectronics,further optimization to increase the lipophilicity and charge density of aromatic substituents of compounds 6d and 7d resulted in compounds 12d,14d and 16d with sulfur–containing heterocycle substituents possessing good insecticidal activity against Musca domestica among the series(LC₅₀=0.67-1.30?g/mL).The thioether bridge N-phenylpyrazole derivatives,which exhibit different length of the spacer arm introduced between N-phenylpyrazole moiety and the?hetero?aromatic substituents,were also prepared and evaluated.By contrast,the insecticidal activities of compounds containing the short thioether bridge,1,2-bis??hetero?aromatic thio?ethane,are higher than that containing the long thioether bridge,1,3-bis??hetero?aromatic thio?propane.For example,the insecticidal activity of compound 13d is 5 times that of the compound28d.The bioassay results showed that the compounds proved to be ineffective against Musca domestica by residual film method.The results of molecular docking and pharmacophore analyses indicated A299,T303,and L306 of Musca domestica?-GABA subunit were essential to form non–covalent interactions contacts with the ligands.Specially,the sulfur–containing heterocycle substituent derivatives 12d and 14d as the sterically favored areas could form the important hydrophobic interactions with the deeper residue P295.