Quantitative structure-activity relationships of mutagenic activity from quantum topological descriptors: triazenes and halogenated hydroxyfuranones (mutagen-X) derivatives.

The mutagenic activity of 23 triazenes and, in a different set, of 24 halogenated hydroxyfuranones (MX derivatives) is quantitatively related to new features of contemporary molecular wave functions. Nowadays affordable computers are powerful enough to rapidly generate geometry-optimised ab initio wave functions at HF/3-21G*, HF/6-31G* and B3LYP/6-311 + G(2d,p) level for all molecules. The bonds of a common molecular skeleton are described by their ab initio bond lengths and local properties provided by the theory of quantum chemical topology (QCT). The chemometric analysis involves two types: one to generate a statistically validated quantitative model, and one to isolate the active center. In the former a genetic algorithm (GA) selects bond descriptors in order to optimise the cross-validation error, q2, followed by a full partial least squares (PLS) analysis, which also yields randomisation statistics. In the latter type principal components (PCs) are constructed from the original bond descriptors and their variables important to the projection (VIPs) are plotted in a histogram. This analysis suggests a preferred mechanistic pathway for the initial hydroxylation of the triazenes, an issue that has remained ambiguous so far. In the case of the hydroxyfuranones the proposed method aids the elucidation of a mechanistic ambivalence.