Mono and bicyclic 6-aminopyridinols and 2-aminopyrimidinols as novel antioxidants and prostaglandin H2 synthase inhibitors
Pyridinol and pyrimidinol analogs of acetaminophen were synthesized as they have modified electronic properties without a significant structural modification. It was observed that inhibition of prostaglandin H2 synthases (PGHSs), or cyclooxygenases (COXs) by acetaminophen and the analogs is dependent on their abilities to donate a hydrogen atom or electron to the oxidized PGHS peroxidase heme. These abilities are reflected in their bond dissociation enthalpies (BDEs) and ionization potentials (IPs). Inhibitory activities of the analogs increased in the higher pH medium where the ionized form of the analogs are predominant, supporting that electron transfer from the analogs to peroxidase heme would be the major contributor to the mechanism of inhibition. Pyridinol and pyrimidinol analogs with dimethylamino substitution that have lower IP and BDE than acetaminophen showed about 10-20 fold better PGHS inhibition than acetaminophen reconfirming the role of electron transfer ability in the inhibitory activities. Reduction of myoglobin heme, which undergoes the similar redox cycle to PGHS peroxidase, by those analogs indicates that they are excellent heme reductants in general. Efficiencies of the compounds in myoglobin heme reduction turned out to be roughly parallel to those in PGHS peroxidase reduction, providing a general and simple prediction of heme reducing efficiency. Unparallel activities were found between pyridinol and pyrimidinol analogs in PGHS peroxidase activation and the isoform selective inhibition which might be due to the different reactivity of the each analog toward peroxidase active site in the PGHS isoforms. It is speculated that structural features of the analogs that can prevent 1,4-addition of glutathione could lead to decrease in the formation of the quinone imine species and the subsequent glutathione adduct formation that is responsible for the hepatotoxicity of acetaminophen. With the excellent inhibitory activity and anticipated less toxicity, these analogs would provide the novel platform for PGHS inhibitors as peroxidase heme reductants.