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. 2022 Mar 21;44(1):10.
doi: 10.1186/s41021-022-00238-1.

A local QSAR model based on the stability of nitrenium ions to support the ICH M7 expert review on the mutagenicity of primary aromatic amines

Ayaka Furukawa  1 , Satoshi Ono  2 , Katsuya Yamada  3 , Nao Torimoto  4 , Mahoko Asayama  3 , Shigeharu Muto  3
Affiliations

A local QSAR model based on the stability of nitrenium ions to support the ICH M7 expert review on the mutagenicity of primary aromatic amines

Ayaka Furukawa et al. Genes Environ. .

Abstract

Background: Aromatic amines, often used as intermediates for pharmaceutical synthesis, may be mutagenic and therefore pose a challenge as metabolites or impurities in drug development. However, predicting the mutagenicity of aromatic amines using commercially available, quantitative structure-activity relationship (QSAR) tools is difficult and often requires expert review. In this study, we developed a shareable QSAR tool based on nitrenium ion stability.

Results: The evaluation using in-house aromatic amine intermediates revealed that our model has prediction accuracy of aromatic amine mutagenicity comparable to that of commercial QSAR tools. The effect of changing the number and position of substituents on the mutagenicity of aromatic amines was successfully explained by the change in the nitrenium ion stability. Furthermore, case studies showed that our QSAR tool can support the expert review with quantitative indicators.

Conclusions: This local QSAR tool will be useful as a quantitative support tool to explain the substituent effects on the mutagenicity of primary aromatic amines. By further refinement through method sharing and standardization, our tool can support the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 expert review with quantitative indicators.

Keywords: Expert review; ICH M7; In silico; Nitrenium ion; Primary aromatic amine; Quantitative structure–activity relationship (QSAR).

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Mechanism of mutagenicity induced by aromatic amines
Fig. 2
Fig. 2
Mutagenicity and ΔΔE distribution of in-house primary aromatic amines. Each bar indicates a compound. Mutagens are shown in red and nonmutagens in green. The aromatic amines are arranged in order of their ΔΔE values (kcal/mol)
Fig. 3
Fig. 3
Effect of activating and deactivating substituents on ΔΔE and mutagenicity of aromatic amines. The structures of mutagens are shown in red and those of nonmutagens in green. The numbers below the structures indicate ΔΔE values. The text in the squares shows the classification by Ahlberg et al
See this image and copyright information in PMC

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