The results of Molecular Orbital (MO) calculations by the MINDO/3 method are reported, together with the results of multiple regression analysis of electronic and structural parameters with inhibition of aniline hydroxylation by a series of 22 alcohols. The most significant correlations show the relationships between molecular length, frontier electron density of the alpha-carbon and hydroxyl oxygen, nucleophilic superdelocalizability of the hydroxyl hydrogen, energy of the highest occupied MO and biological activity involving binding to microsomal cytochromes P-450. Using the data of Cohen and Mannering (Mol. Pharmacol., 9 (1973) 383), Testa, (Chem.-Biol. Interact., 34 (1981) 287) has shown that the inhibition of aniline hydroxylation by a series of alcohols can be related to their electronic structure and hydrophobicity (measured by log P, the octanol-water partition coefficient). The mode of binding and effect on spin-state equilibria in cytochrome P-450 by alcohols has been elucidated by Testa, whereas an alternative hypothesis based on connectivity correlations has been reported by Sabljic and Sabljic (Mol. Pharmacol., 23 (1983) 213). The present work shows that the biological response can be explained by calculated electronic structure and molecular shape parameters. Also, one compound (the only tertiary alcohol) from the original set that was not included in Testa's calculations and analysis, is included in this work and its activity successfully calculated. The latter authors, Sabljic and Sabljic, were led to exclude the data for this compound and one other (phenyl methanol) in order to achieve a good correlation with their calculated parameters of molecular structure.
Cytology and Cytochemistry-General; Ecology; Biochemical Studies-General; Biochemical Studies-Proteins; Biochemical Studies-Porphyrins and Bile Pigments; Biophysics-Molecular Properties and Macromolecules; Biophysics-Membrane Phenomena; Enzymes-General and Comparative Studies; Metabolism-General Metabolism; Toxicology-General; Toxicology-Environmental and Industrial Toxicology; Public Health: Environmental Health-Air