Nagaoka Hikaru, Nishiwaki Hisashi, Kubo Takuya, Akamatsu Miki, Yamauchi Satoshi, Shuto Yoshihiro
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
Bioorg Med Chem. 2015 Feb 15;23(4):759-69. doi: 10.1016/j.bmc.2014.12.058. Epub 2015 Jan 3.
In the present study, nitromethylene neonicotinoid derivatives possessing substituents that contain a sulfur atom, oxygen atom or aromatic ring at position 5 on the imidazolidine ring were synthesized to evaluate their affinity for the nicotinic acetylcholine receptor (nAChR) and their insecticidal activity against adult female houseflies. Comparing the receptor affinity of the alkylated derivative with the receptor affinity of compounds possessing either ether or thioether groups revealed that conversion of the carbon atom to a sulfur atom did not influence the receptor affinity, whereas conversion to an oxygen atom was disadvantageous for the receptor affinity. The receptor affinity of compounds possessing a benzyl or phenyl group was lower than that of the unsubstituted compound. Analysis of the three-dimensional quantitative structure-activity relationship using comparative molecular field analysis demonstrated that steric hindrance of the receptor should exist around the C3 of an n-butyl group attached at position 5 on the imidazolidine ring. A docking study of the nAChR-ligand model suggested that the ligand-binding region expands as the length of the substituent increases by brushing against the amino acids that form the binding region. The insecticidal activity of the compounds was positively correlated with the receptor affinity by considering logP and the number of heteroatoms, including sulfur and oxygen atoms, in the substituents, suggesting that the insecticidal activity is influenced by the receptor affinity, hydrophobicity, and metabolic stability of the compounds.
在本研究中，合成了在咪唑烷环的5位具有含硫原子、氧原子或芳香环取代基的硝基亚甲基新烟碱衍生物，以评估它们对烟碱型乙酰胆碱受体（nAChR）的亲和力以及对成年雌性家蝇的杀虫活性。将烷基化衍生物的受体亲和力与具有醚基或硫醚基的化合物的受体亲和力进行比较，结果表明碳原子转化为硫原子不会影响受体亲和力，而转化为氧原子则对受体亲和力不利。具有苄基或苯基的化合物的受体亲和力低于未取代的化合物。使用比较分子场分析对三维定量构效关系进行分析表明，在咪唑烷环5位连接的正丁基的C3周围应存在受体的空间位阻。对nAChR-配体模型的对接研究表明，随着取代基长度的增加，配体结合区域通过与形成结合区域的氨基酸发生摩擦而扩大。考虑到logP以及取代基中包括硫和氧原子在内的杂原子数量，化合物的杀虫活性与受体亲和力呈正相关，这表明杀虫活性受化合物的受体亲和力、疏水性和代谢稳定性的影响。
