In silico and in vitro assessments of the mutagenicity of the azilsartan photoproduct

Photodegradation of azilsartan yields a phenanthridine derivative (APP). We suspected that APP could be a DNA-reactive substance, since many phenanthridine derivatives are mutagenic. In silico quantitative structure-activity relationship analysis indicated potential mutagenicity of APP, due to DNA reactivity at the 6-aminophenanthridine moiety. However, APP was not mutagenic in the Ames test. Density functional theory (DFT) calculations showed that APP cannot intercalate into DNA, due to its nonplanar structure, resulting from steric hindrance of its phenanthridine and benzimidazole moieties.