Quantitative structure-activity relationship of substituted imidazothiadiazoles for their binding against the ecdysone receptor of Sf-9 cells.
Quantitative structure-activity relationship of substituted imidazothiadiazoles for their binding against the ecdysone receptor of Sf-9 cells.
复制标题
取代咪唑并噻二唑与 Sf-9 细胞蜕皮激素受体结合的定量构效关系。
DOI：
10.1016/j.bmcl.2017.10.013
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Hisashi Miyagawa
中科院分区：
文献类型：
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作者：
Taiyo Yokoi;Yoshiaki Nakagawa;Hisashi Miyagawa
咪唑噻二唑类化合物是一类具有杀幼虫活性的非甾体蜕皮激素激动剂。先前，我们对ITD类似物进行了Hansch-Fujita类型的定量结构-活性关系（QSAR）分析（Yokoi等人，Pestic。Biochem.Physiol.2015，120，40-50）。用咪唑并噻二唑环上取代基的疏水性和电负性合理地解释了活性。然而，有限的数据点（n= 8）妨碍了其他理化参数的检查。在本研究中，我们扩大了ITD同源物库，并使用完整的Sf-9细胞评估其受体结合亲和力。扩展集的QSAR分析揭示了第三个物理化学参数，长取代基的负空间效应的意义。我们还评估了所合成的化合物对斜纹夜蛾的杀幼虫活性;然而，它与结合亲和力不相关。结果表明，要提高ITDs的杀幼虫活性，必须改善ITDs的药代动力学特性。
Imidazothiadiazoles (ITDs) are a class of potent nonsteroidal ecdysone agonists with larvicidal activity. Previously, we performed the Hansch–Fujita type of quantitative structure–activity relationship (QSAR) analysis for ITD analogs (Yokoi et al.,Pestic. Biochem. Physiol.2015,120, 40–50). The activity was reasonably explained by hydrophobicity and electronegativity of substituents on the imidazothiadiazole ring system. However, the limited data points (n= 8) hampered the examination of other physicochemical parameters. In the present study, we expanded the library of ITD congeners and evaluated their receptor-binding affinity using intact Sf-9 cells. The QSAR analysis for the expanded set revealed the significance of the third physicochemical parameter, the negative steric effect for long substituents. We also evaluated the larvicidal activity of the synthesized compounds against Spodoptera litura; however, it was not correlated to the binding affinity. The results obtained here suggests that the pharmacokinetic properties must be improved to enhance the larvicidal activity of ITDs.