Herein we report an investigation of the efficacy of
pyridine and
pyrimidine analogs of
acetaminophen (
ApAP) as
peroxyl radical-trapping
antioxidants and inhibitors of
enzyme-catalyzed lipid peroxidation by
cyclooxygenases (COX) and
lipoxygenases (LOX). In inhibited autoxidations we find that
ApAP, the common
analgesic and
antipyretic agent, is a very good
antioxidant with a rate constant for reaction with peroxyl radicals (k(inh) = 5 x 10(5) M(-1) s(-1)) that is higher than many widely-used phenolic
antioxidants, such as the ubiquitous
butylated hydroxytoluene (
BHT). This reactivity is reduced substantially upon incorporation of
nitrogen into the phenolic ring, owing to an increase in the O-H bond dissociation enthalpy of pyridinols and pyrimidinols with respect to
phenols. Incorporation of
nitrogen into the phenolic ring of
ApAP was also found to decrease its efficacy as an inhibitor of
prostaglandin biosynthesis by ovine COX-1 (oCOX-1). This is explained on the basis of an increase in its oxidation potential and its reduced reactivity as a reducing co-substrate of the
peroxidase protoporphyrin. In contrast, the efficacy of
ApAP as an inhibitor of
lipid hydroperoxide biosynthesis by soybean LOX-1 (sLOX-1) increased upon incorporation of
nitrogen into the ring, suggesting a different mechanism of inhibition dependent on the acidity of the phenolic O-H which may involve chelation of the catalytic non-
heme iron atom. The greater stability of the 3-pyridinols and 5-pyrimidinols to air oxidation as compared to
phenols allowed us to evaluate some electron-rich pyridinols and pyrimidinols as inhibitors of oCOX-1 and sLOX-1. While the pyridinols had the best combination of activities as
antioxidants and inhibitors of oCOX-1 and sLOX-1, they were found to be more toxic than
ApAP in preliminary assays in human
hepatocellular carcinoma (HepG2) cell culture. The pyrimidinols, however, were up to 17-fold more reactive to peroxyl radicals and up to 25-fold better inhibitors of
prostaglandin biosynthesis than
ApAP, with similar cytotoxicities to HepG2 cells at high levels of exposure.