The definition of the toxicologically relevant applicability domain for the S_NAr reaction for substituted pyridines and pyrimidines

Abstract

This study outlines how results from a glutathione reactivity assay (so-called in chemico data) can be used to define the applicability domain for the nucleophilic aromatic substitution (S_NAr) reaction for nitrogen-containing aromatic compounds. S_NAr is one of the six mechanistic domains that have been shown to be important in toxicological endpoints in which the ability to bind covalently to a protein is a key molecular initiating event. This study has analysed experimental data (2 h RC₅₀ values), allowing a clear and interpretable structure–activity relationship to be developed for pyridines and pyrimidines which reside within the S_NAr domain. The in-ring nitrogen(s) act as activating groups in the S_NAr reaction. The position(s) of the in-ring nitrogen(s) as well as other activating groups, especially in relationship to the leaving group, affect reactive potency. The experimentally defined applicability domain has resulted in a series of structural alerts. These results build on early work on the benzene derivatives residing in the S_NAr domain. The definition of the applicability domain for the S_NAr reaction and the resulting structural alerts are likely to be beneficial in the development of computational tools for category formation and read-across in hazard identification, and the development of adverse outcome pathways.

Keywords:

• in chemico
• S_NAr
• structural alerts
• electrophilic reaction chemistry
• adverse outcome pathways

Acknowledgements

The funding of the European Chemicals Agency Service Contract No. ECHA/2008/20/ECA.203 is gratefully acknowledged. The project was sponsored by Defra through the Sustainable Arable Link Program. The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007-2013) COSMOS Project under grant agreement number 266835 and from Cosmetics Europe.

Notes

Presented at the 15th International Workshop on Quantitative Structure-Activity Relationships in Environmental and Health Sciences (QSAR2012), 18-22 June 2012, Tallinn, Estonia.