Structural cytotoxicity relationship of 2-phenoxy(thiomethyl)pyridotriazolopyrimidines: Quantum chemical calculations and statistical analysis

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.