ABSTRACT
Chemically reactive metabolites can react with DNA, proteins, or other molecules leading to mutations, cancer, birth defects, and a variety of other types of toxicity. It is important to understand the pathways that can lead to reactive metabolites and to be able to predict when a specific metabolite will be chemically reactive. Sulfamethoxazole is an antibiotic that also undergoes N-oxidation followed by acetylation; however, the electron-withdrawing effect of the para sulfonamide group makes it too difficult to form a nitrenium ion. Methylenedioxy compounds such as piperonyl butoxide are used to make insecticides more effective by inhibiting the insect enzymes that inactivate the insecticide. Several functional groups such as aryl amines/aryl nitro groups, thiophenes, furans, and 3-methylindoles. are considered “structural alerts” and are often avoided when synthesizing drug candidates. In vitro studies are easier to perform, but they may produce misleading results because the enzyme responsible for bioactivation and/or detoxifying systems may be absent.
