Valuation Of Efficacy And Cross-Resistance To Neonicotinoid Analogues

With the successful development of the first neonicotinoid insecticide imidacloprid, researches of the functional group transformation were carried out and developed a series of neonicotinoid insecticides, such as thiacloprid, thiamethoxam, dinotefuran and sulfoxaflor. Based on the structure of imidacloprid, a series of analogues were also synthesized in China, which biological activities need to be detected.Neonicotinoid insecticides act on insect nicotinic acetylcholine receptors (nAChRs). The (-NO2) or (-CN) group in all commercial neonicotinoid is at trans-configuration, like imidacloprid and thiamethoxam. Some potential neonicotinoids with fused heterocycles or bulky groups fixed c/s-configuration have been synthesized and showed insecticidal activity against a wide range of insects.As a new neonicotinoid insecticide with-NO2 at cis-configuration position, cycloxaprid shows higher activity than imidacloprid and is likely to become an important novel insecticide. Using imidacloprid and cycloxaprid as the leading compound, imidacloprid and cycloxaprid analogues were developed by the functional groups transforming and structure optimizing. In this paper, efficacy and cross-resistance of imidacloprid and cycloxaprid analogues were evaluated, and the mechanism of imidacloprid analogue IPP165059 was studied.1. Toxicity evaluation of imidacloprid and its analoguesImidacloprid analogues were obtained by addition reactions based on imidacloprid, including NJm455 series, NJm403 series and NJmb51 series.Toxicity evaluation of 18 analogues showed that NJm455A, NJm4033 and NJmb514 were the most efficient compound of each series respectively. However, compard with imidacloprid, corrected mortality of these three insecticides was significant lower at the dose of 40ng/insect. We gave up the further tests on these analogues.2. Efficacy and cross-resistance evaluation of imidacloprid series and cycloxaprid series compoundsIn this paper, toxicities of imidacloprid, cycloxaprid and four novel compounds were evaluated in susceptible and resistant strains. In susceptible strains, all these novel compounds showed lower LD50 values than their corresponding leading compounds. IPP165059 and IPP165030 showing significant cross-resistance with imidacloprid indicated these two compounds might have the same or similar mechanism of action. Moderate levels of cross-resistance to imidacloprid were found in IPP165026 and IPP165029. In contrast, there was no significant cross-resistance between cycloxaprid and imidacloprid. These results indicated that substitution of Cl by H/F/-CH3 on pyridyl would increase the efficacy, but resulted in serious cross-resistance.3. Mechanisms of IPP165059In order to understand its mechanism, the efficacy of IPP 165059 on hybrid receptors Nlα1/｛2 was tested in Xenopus oocytes using two-electrode voltage clamp. The response was detected after IPP 165059 application and could be inhibited by typical nAChRs inhibitor ML A and DhβE, which demonstrated IPP 165059 was an agonist on hybrid receptors.Y151S mutant was derived from the laboratory strain of brown planthopper (screening over 30 generations by imidacloprid) located on Nlal agonist binding site and had been proved to be related to imidacloprid resistance. Heterologous expression and electrophysiological results showed that the Y151S mutation in NIα1/β2 caused a 3.53-fold increase in EC50 values of IPP165059 and the fold was 2.38 for imidacloprid, which showed the sensitivity of IPP 165059 was more influenced by the mutation than imidacloprid.