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.

本研究探究了嘧啶衍生物（pyrimidine derivatives）对埃及伊蚊（Aedes aegypti）的生物活性，其中化合物3c与3d展现出优异的杀幼虫活性。此外，本研究分别基于Dragon与VolSurf+软件生成的分子描述符，采用多元线性回归与偏最小二乘算法构建了定量构效关系（quantitative structure-activity relationship, QSAR）模型；其中由多元线性回归（multiple linear regression, MLR）构建的模型为最优模型，具备良好的稳健性。为评估该模型在预测针对埃及伊蚊杀幼虫活性时的可靠性、准确性与稳健性，本研究通过多种内部验证方法对其开展了验证。模型结果表明，嘧啶衍生物的三维分子结构、空间性质、疏水极性表面积、脂水分配系数（log partition coefficient, logP），以及其所含甲基、甲氧基、琥珀酰亚胺等取代基的简单排布模式，是决定该类化合物杀幼虫活性的关键因素。进一步研究发现，当R1位存在吸电子基团时，化合物活性会降低；若将该基团替换为芳环活化基团，则活性显著提升。本研究结果可为后续开发新型抗埃及伊蚊的嘧啶衍生物提供理论支撑与指导。