Design, Synthesis And Bioassay Of Azabridged Neonicotinoid Compounds

Two decades of increasing use, neonicotinoids have established their important role in crop protecting and animal health. However, the potential factors of growing resistance and high bee-toxicity have restricted the development of neonicotinoid insecticides. Therefore, it was necessary to explore novel compounds with new structure and mode of action (MoA). In this thesis, seven-membered and eight-membered azabridged neonicotinoid compounds were designed and synthesized, with the prospect of obtaining high insecticidal activities.1. The molecular docking between Cycloxaprid (CYC) and Ac-AChBP has showed that the bridged oxygen atom was pointing the gap of two amino-acid residues, which inspired us to expand structure from the bridged atom in order to increase the interaction between molecular and the receptors. Owing to the oxygen atom can not be modified any more, therefore, the molecular design of azabridged neonicotinoid compounds were carried out.2. The commercialized glutaraldehyde and various types of primary amine hydrochlorides were firstly chosen to synthesize42eight-membered azabridged neonicotinoid compounds. All of the target compounds were obtained in optimized reaction conditions. The tested compounds displayed high toxicity to honey bees. Most of eight-membered azabridged compounds exhibited higher insecticidal activities than eight-membered oxabridged compound B against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker) and brown planthopper (Nilaparvata lugens). Compared with Imidacloprid (IMI), some azabridged compounds exhibited excellent insecticidal activity against brown planthopper.3. When synthesizing azabridged neonicotinoid compounds, the azo-neonicotinoid analogues was discoveried. By synthesizing15N labeled compund, it was confirmed that the second nitrogen atom was from the nitro group of starting material A. According to the experiments and literatures, possible mechanism was also proposed.4.51novel seven-membered azabrigded neonicotinoid analogues were synthesized through two preparation methods of succinaldehyde. On the basis of the optimation results of eight-membered compounds, the appropriate reaction conditions and temperature were used to synthesize seven-membered azabridged neonicotinoid compounds. The tested compounds presented high toxicity to honey bees. Most of seven-membered azabridged compounds exhibited higher insecticidal activities than seven-membered oxabridged compound CYC against cowpea aphid, brown planthopper, and armyworm, which proved that introducing the framework of seven-membered azabridge, was an effective strategy to discover new potential high activities compounds.5. To modify seven-membered oxa-or aza-bridge ring by using intra-molecular way, a new method to synthesize pyrrolo[1,2-a]imidazole analogues was confirmed and discussed the possible mechanism of formation. Comparing with other synthetic methodology, the newly discovered way has the characteristics of less synthesis steps, smooth reaction condition, and high yields, which was an important method in the synthesizing of biopharmaceutical industry.