Bioactivation structural alerts

Figure 15.1 Compilation of structural alerts/toxicophores known to undergo bioactivation and examples of hepatotoxic drugs containing the structural alerts.

A second example is evident from the work of Singh et al.68 on the pyrazinone-containing thrombin inhibitor 2, which is associated with irreversible incorporation of radioactivity to human microsomal tissue and in vivo in the rat. Visual inspection of the structure as well as analysis in the DEREK program does not raise any concern with regards to the presence of structural alerts. However, mechanistic studies on reactive metabolite formation depict de novo metabolic routes of bioactivation on the latent pyrazinone-ring system, leading to the formation of reactive metabolites that adduct to GSH (Figure 6.6). 

With the exception of trovafloxacin, none of the other drugs in the fluoroquinolone class of antibiotics have been associated with idiosyncratic hepatotoxicity. From a structure-toxicity standpoint, it is interesting to note the presence of the cyclopropylamine structural alert at the C7 position of the fluoroquinolone scaffold in trovafloxacin. Studies with a model compound have revealed cyclopropylamine ring bioactivation by CYP and myeloperoxidase to a reactive a,P-unsaturated aldehyde trapped as a sulfydryl conjugate... 

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