The role of regioselective hydroxylation on toxicity of diclofenac and related derivatives

Abstract

ABSTRACTDiclofenac and related derivatives become more toxic after biotransformation reactions in the body by electron or hydrogen transfers. The structure–reactivity study on regioselective hydroxylation of diclofenac acid was elucidated by using quantum chemistry calculations at level of DFT/B3LYP/6-31G(d,p). HOMO, ionisation potential, bond dissociation energy, and spin density distributions were used as chemical reactivity parameters. Also, some properties are related to lumiracoxib and fenclofenac. The higher flexibility of lumiracoxib can be responsible for the increase of COX2 selectivity. Diphenyl-amine moiety is responsible for their potent antioxidant capacity. Chloro atoms have a strong effect under electron transfer capacity when compared to acetic acid group. Hydroxylation for the 5-hydroxydiclofenac is more favoured in either electron or hydrogen transfers. Both hydroxylation increased the electron donation and antioxidant capacity. These properties were observed to the fenclofenac derivatives and can be related to their toxicity by redox mechanism.