Experimental Testing of Quantum Mechanical Predictions of Mutagenicity: Aminopyrazoles

Abstract

A computational method for predicting the likelihood of aromatic amines being active in the Ames test for mutagenicity was trialed on a set of aminopyrazoles. A virtual array of compounds was generated from the available sets of hydrazines and α-cyanoaldehydes (or ketones) and quantum mechanical calculations used to compute a probability of being active in the Ames test. The compounds selected for synthesis and testing were not based on the predictions and so spanned the range of predicted probabilities. The subsequently generated results of the Ames test were in good correspondence with the predictions and confirm this approach as a useful means of predicting likely mutagenic risk.

In silico predictions of genotoxicity for aromatic amines

“…In this review we showed that for the class of primary aromatic amines a mechanism based ab initio approach, the nitrenium hypothesis, can be used to successfully classify Ames positive and Ames negative compounds. The fact that major pharmaceutical companies have published on this approach (54,(56)(57)(58)(59)(60) is evidence that this technology has come a long way since its early publications by Ford and Griffin (46)(47). The appealing characteristic of this first principal approach is that, unlike QSAR methods, it does not rely on the identification of a training set.…”

Density Functional Theory in the Prediction of Mutagenicity: A Perspective

“…Following this in 2013, Leach et al carried out a set of Ames test procedures on a virtual array of aminopyrazoles, and in parallel, used DFT to predict the associated probability of being positive in the Ames test. 67 The dissociation energy ΔE was calculated for a variety of activated aminopyrazole conjugates at the B3LYP/6-31G* level of theory. The probabilistic results generated from DFT calculations showed excellent promise for predicting the risk of mutagenic activity in the Ames test.…”

“…An unsuitable choice of nucleophile for examination in transition states could drastically affect the predictive performance of a model. Following this in 2013, Leach et al carried out a set of Ames test procedures on a virtual array of aminopyrazoles, and in parallel, used DFT to predict the associated probability of being positive in the Ames test . The dissociation energy Δ E was calculated for a variety of activated aminopyrazole conjugates at the B3LYP/6-31G* level of theory.…”

The role of intramolecular self‐destruction of reactive metabolic intermediates in determining toxicity

“…For the thiazides, the lack of aryl amine characteristic toxicity could be related to the almost exclusive renal elimination of the unchanged drug among the representatives used in doses of 100 mg or above (Leach et al , ). Only bendroflumethiazid ( 114e ) and polythiazide ( 114d ) are metabolized to a significant degree, 70% and 75% (Dollery, ; Leach et al , ), respectively, but are recommended in doses far below 100 mg.…”

“…Far from all aryl amines are toxic even if lacking a moiety competent of quenching the N ‐oxy group of the corresponding metabolite (Shamovsky et al , ; Leach et al , ). Although the formation of five‐ and six‐membered lactones, lactams, hemiacetals, hemiketals and structurally reminiscent functionalities are generally rapidly and readily formed, their formation cannot be proved for each drug metabolite with the data at hand.…”