Pyrimidine Derivatives: QSAR Studies of Larvicidal Activity against Aedes aegypti

The present study investigated the activity of pyrimidine derivatives against Aedes aegypti. Two compounds, 3c and 3d showed excellent larvicide activity. Additionally, quantitative structure-activity relationship (QSAR) models were built using multiple-linear regression and partial least squares with descriptors generated from Dragon and VolSurf+ software, respectively. The best model is obtained with multiple linear regression (MLR), leading to a robust model. Moreover, the QSAR model is validated by means of some internal validation techniques in order to check its reliability, quality and robustness for predicting the larvicidal activity against A. aegypti. The models confirmed that the three-dimensional structure of molecules, steric properties, hydrophobic polar surface area, log partition (logP) and a simple pattern of substituent groups as methyl, methoxy, and succinimide in the pyrimidine derivatives are responsible for the larvicidal activity of the pyrimidine derivatives. Even more, the activity decreases by an electron-withdrawing group in R1 and increases when it is replaced by an aromatic ring activator group. These findings will aid in further studies of new pyrimidine derivatives active against Aedes aegypti.

本研究考察了嘧啶类衍生物对埃及伊蚊（Aedes aegypti）的杀虫活性，其中化合物3c与3d展现出优异的杀幼虫活性。此外，本研究分别采用多元线性回归与偏最小二乘法构建定量构效关系（quantitative structure-activity relationship, QSAR）模型，多元线性回归模型的特征描述符由Dragon软件生成，偏最小二乘模型的特征描述符则由VolSurf+软件生成。其中，由多元线性回归（multiple linear regression, MLR）构建的模型为最优模型，其稳健性优异。进一步地，本研究采用多种内部验证技术对该QSAR模型进行验证，以评估其在预测埃及伊蚊杀幼虫活性时的可靠性、建模质量与稳健性。模型证实，嘧啶类衍生物的分子三维结构、空间位阻性质、疏水极性表面积、分配系数对数（log partition, logP），以及甲基、甲氧基、琥珀酰亚胺类取代基的简单排布模式，是决定其杀幼虫活性的核心因素。研究还发现，若R1位引入吸电子基团，化合物的杀幼虫活性会随之降低；而当该位点被芳环活化基团取代时，活性则会显著提升。上述研究成果可为后续开发针对埃及伊蚊的新型活性嘧啶类衍生物提供重要的理论参考与指导。