Abstract Previously, a series of pyridotriazolopyrimidines (1–6) were synthesized and fully described. The target compounds (1–6) were evaluated for their cytotoxicity against MCF-7, HepG2, WRL 68, and A549 (breast adenocarcinoma, hepatocellular carcinoma, embryonic liver, and pulmonary adenocarcinoma, respectively) cell lines using MTT assay. The tested compounds demonstrated cytotoxicity, but no significant activity. To elucidate the structure–cytotoxicity relation of the prepared pyridotriazolopyrimidines, several chemical descriptors were determined, including electronic, steric, and hydrophobic descriptors. These chemical descriptors were calculated in the polarizable continuum model (water as solvent) using density functional theory calculations at B3LYP/6-31+G(d,p). By employing simple linear regression (SLR) and multiple linear regression (MLR) analyses, the impact of the selected descriptors was assessed statistically. The obtained results clearly reveal that the cytotoxicity of pyridotriazolopyrimidines depends on their (i) basic skeleton and (ii) the type of the tested cell. Interestingly, SLR and MLR analyses show that the impact of the selected descriptors is strongly related to the tested cells and basic skeleton of the tested compounds. For instance, the cytotoxicity of subclasses 2a and 2c–2f against A459 shows strong correlation with ionization potential, hardness (η), and hydrophobicity (log P) with a correlation coefficient of 99.86% and a standard deviation of 0.53.

中文翻译：

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2-苯氧基（硫甲基）吡啶并三唑并嘧啶的结构细胞毒性关系：量子化学计算和统计分析

摘要 此前，合成并充分描述了一系列吡啶并三唑并嘧啶 (1-6)。使用 MTT 测定评估目标化合物 (1-6) 对 MCF-7、HepG2、WRL 68 和 A549（分别为乳腺癌、肝细胞癌、胚胎肝和肺腺癌）细胞系的细胞毒性。测试的化合物显示出细胞毒性，但没有显着的活性。为了阐明所制备的吡啶并三唑并嘧啶的结构-细胞毒性关系，确定了几种化学描述符，包括电子、空间和疏水描述符。这些化学描述符是在可极化连续介质模型（水作为溶剂）中使用密度泛函理论计算在 B3LYP/6-31+G(d,p) 中计算的。通过采用简单线性回归 (SLR) 和多元线性回归 (MLR) 分析，对所选描述符的影响进行了统计评估。获得的结果清楚地表明，吡啶并三唑并嘧啶的细胞毒性取决于它们的 (i) 基本骨架和 (ii) 测试细胞的类型。有趣的是，SLR 和 MLR 分析表明，所选描述符的影响与测试的细胞和测试化合物的基本骨架密切相关。例如，亚类 2a 和 2c-2f 对 A459 的细胞毒性显示出与电离电位、硬度 (η) 和疏水性 (log P) 的强相关性，相关系数为 99.86%，标准偏差为 0.53。获得的结果清楚地表明，吡啶并三唑并嘧啶的细胞毒性取决于它们的 (i) 基本骨架和 (ii) 测试细胞的类型。有趣的是，SLR 和 MLR 分析表明，所选描述符的影响与测试的细胞和测试化合物的基本骨架密切相关。例如，亚类 2a 和 2c-2f 对 A459 的细胞毒性显示出与电离电位、硬度 (η) 和疏水性 (log P) 的强相关性，相关系数为 99.86%，标准偏差为 0.53。获得的结果清楚地表明，吡啶并三唑并嘧啶的细胞毒性取决于它们的 (i) 基本骨架和 (ii) 测试细胞的类型。有趣的是，SLR 和 MLR 分析表明，所选描述符的影响与测试的细胞和测试化合物的基本骨架密切相关。例如，亚类 2a 和 2c-2f 对 A459 的细胞毒性显示出与电离电位、硬度 (η) 和疏水性 (log P) 的强相关性，相关系数为 99.86%，标准偏差为 0.53。