Design, Synthesis And Bioactivity Of Neonicotinoids And EBF Analogues

As one kind of the most important pests in the world, aphids have great number of species, can fast breed and seriously spread the plant virus. To efficiently control aphids lead to the increasing of dosage and frequency of insecticide, which are influencing the food security and ecological environment safety.Thus, it is urgent to discover new aphid control agent with new mechanism.Acting on insect nicotinic acetylcholine receptors (nAChRs), neonicotinoid insecticides have been rapidly developed worldwide because of their high potency, low mammalian toxicity, broad insecticidal spectra and good systemic properties. However, overuse of neonicotinoid insecticides has brought about some serious ecological problems, such as high-level resistance and bee toxicity. Thus, it is necessary to find alternative products to overcome the above problems.(E)-?-farnesene (EBF) is one important kind of alarm pheromones, which is released by most aphids when they were disturbed. EBF is endowed with multiple biological functions, such as repellent and aphicidal activities. Owing to the advantages such as low dosage, specificity and safety to non-target organisms and environment, EBF attracts more attention from scientists in plant protection. But EBF is easily oxidized because of the unstable conjugated double bonds in its molecule, which limits its application in the field. In our previous work, the structure of EBF has been optimized in multi-aspect and some novel EBF analogues with both pleasant activity and high stability have been discovered for further work.To discover novel aphicides with high activity, low toxicity and favorable safety profile, and systemically study on their structure-activity relationship, commercial neonicotinoid insecticides as well as (E)-?-farnesene were chosen as the potential lead compounds for further modification in this thesis.The discoveries and results were mainly described as follows:(1) Novel neonicotinoid analogues have been designed and synthesized on the basis of commercial pesticides. Two series of neonicotinoid analogues containing oxazole group or hydrazide group were obtained and their biological activity was evaluated. The result of bioassay showed that ?-02 and ?-03 had the comparable insecticidal activity with clothianidin. Besides, some compounds also displayed good fungicidal activities. Molecular docking and SAR studies revealed that target compounds ?containing hydrazide group had a similar mode of action to clothianidin, and substituent R2 also played an important role in insecticidal activity. Increase in number of carbon atoms or introduction of phenyl group lead to the activity decline because of the higher bulk or steric hindrance of the substituent. In other words,a small sized R2 group is conducive to the bioactivity. However,oxazolyl group may be more useful for designing molecules with fungicidal activity.(2) Replacing the unstable conjugated double bonds of EBF with s-triazine ring, benzoylurea group,oxime ether,cinnamic aldehyde and oxalate substituents respectively,five series of EBF analogues were designed and synthesized. Insecticidal activity results indicated that most compounds, especially compounds containing s-triazine or benzoylurea group, exhibited better aphicidal activity against Aphis glycines than (E)-?-farnesene. And some compounds, such as ?-A01. ?-A03. ?-A04 and ?-A05,showed comparative insecticidal activity with imidacloprid. Behavior experiments results indicated that some of the tested compounds which containing cinnamic aldehyde and oxalate group, such as VI-02?-04.?-15 and ?-18,showed obvious repellent activities against Myzus persicae, less than(E)-?-farnesene, but their stability were higher than (E)-?-farnesene.(3) The relationship between EBF analogues and their bioactivities was studied from the aspects of structure, physicochemical properties and logP values for the first time. When containing the pharmacophore of insecticide and logP value less than 4.7, the analogues tended to insecticidal activity.While the structure similar to EBF, with the melting point below 40 ? or as an oil, and logP value higher than 5.3, the analogues would possess repellent activity. In addition, the influence of dose and repellent time of EBF analogues to their bioactivities was also studied. Regularly, the compounds would perform obvious repellent effect after 15 min under 5?10 ?g dosage.In conclusion, seven series of 115 novel analogues were designed and synthesized by the method of linking active substructures. All the structures of target compounds were identified through 1H NMR,IR,HRMS or elemental analysis. Some target compounds showed favorable bioactivities,better stability and lower toxicity. The relationship between structure and activity was systematically explored through the molecular docking and SAR, which could be instructive for the creation of new aphid control agents.