Nitro-aromatic compounds metabolic activation

Fig. 10.2 Metabolic activation pathways leading to mutation in nitro-aromatic compounds. Ring-oxidation might occur in the ortho, meta, or para position. Shown in the figure is the para metabolic ring-oxidation. Figure adapted from [15]...

A QSAR model was developed to test the mutagenicity of 117 nitro-aromatic compounds in bacterial strain cells without metabolic activation [74]. It was shown that hydrophobicity plays a crucial role in determining the relative mutagenicity of most of the compounds studied. The mutagenicity of the nitro-aromatic compounds increases slowly at low logR and then decreases rapidly at high log P. It was suggested that a combination of adverse hydrophobic and steric effects could explain these observations. In a subsequent analysis, Debnath and Hansch [75]... 

Fortunately, there is now a comprehensive body of knowledge on the metabolic reactions that produce reactive (toxic) intermediates, so the drug designer can be aware of what might occur, and take steps to circumvent the possibility. Nelson (1982) has reviewed the classes and structures of drugs whose toxicities have been linked to metabolic activation. Problem classes include aromatic and some heteroaromatic nitro compounds (which may be reduced to a reactive toxin), and aromatic amines and their N-acylated derivatives (which may be oxidized, before or after hydrolysis, to a toxic hydroxylamine or iminoquinone). These are the most common classes, but others are hydrazines and acyl-hydrazines, haloalkanes, thiols and thioureas, quinones, many alkenes and alkynes, benzenoid aromatics, fused polycyclic aromatic compounds, and electron-rich heteroaromatics such as furans, thiophenes and pyrroles. 

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