SAR MODELS FOR METABOLIC-ACTIVATION - STABILITY OF ORGANIC CATION INTERMEDIATES

Semi-empirical methods for estimating the stability of organic cations through hydride abstraction or protonation were evaluated. To simulate hydride abstraction, stability was defined as the difference between the calculated enthalpies of the cations and the parent structures. Cations formed by protonation were compared to proton affinities by computing enthalpies of the conjugate acids and the corresponding bases. Semi-empirical quantum chemical methods, including AM1, PM3 and MNDO hamiltonians, were used to evaluate their capability to model reaction enthalpies and estimate cation stability. All three methods were acceptable in estimating the stability of cations obtained by hydride abstraction. The correlation coefficients between computed stabilities from the three methods and measured stabilities ranged from 0.83 for MNDO to 0.92 for AM1. The AM1 method was the only acceptable hamiltonian for estimating proton affinity for the studied chemicals. The correlation coefficient between measured and computed values was 0.89. The models for stability will be incorporated into larger QSAR activation models for estimating the probability of mutagenicity and tumor formation in risk assessments.