Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity?

Mutagenesis. 2019 Mar 6;34(1):67-82. doi: 10.1093/mutage/gey020.


(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class. This article analysed a series of publicly available aromatic N-oxide data in search of supporting information. The article also used a previously developed structure-activity relationship (SAR) fingerprint methodology where a series of aromatic N-oxide substructures was generated and matched against public and proprietary databases, including pharmaceutical data. An assessment of the number of mutagenic and non-mutagenic compounds matching each substructure across all sources was used to understand whether the general class or any specific subclasses appear to lead to mutagenicity. This analysis resulted in a downgrade of the general aromatic N-oxide alert. However, it was determined there were enough public and proprietary data to assign the quindioxin and related chemicals as well as benzo[c][1,2,5]oxadiazole 1-oxide subclasses as alerts. The overall results of this analysis were incorporated into Leadscope's expert-rule-based model to enhance its predictive accuracy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cyclic N-Oxides / chemistry*
  • Cyclic N-Oxides / toxicity
  • DNA Damage / drug effects*
  • Mutagenesis / drug effects
  • Mutagenicity Tests
  • Mutagens / chemistry*
  • Mutagens / toxicity
  • Quantitative Structure-Activity Relationship*


  • Cyclic N-Oxides
  • Mutagens