Synthesis and photophysical properties of deuteration of pirfenidone

Abstract

In order to improve the metabolism of pirfenidone (5-methyl-1-phenylpyridin-2-one, PFD), the methyl-deuterated version of pirfenidone via the substitution of hydrogen (H) at C-5 by its isotope deuterium (D, 5D-PFD) was synthesized and its photophysical properties were investigated. The negative solvatochrom was observed in absorption and fluorescence spectra with increasing solvent polarity, which implied that intermolecular charge transfer (ICT) involved n → π* transition for both of PFD and 5D-PFD. The ground state and excited state dipole moment was calculated as 5.30 D and 3.30 D for PFD, and 3.70 D and 2.18 D for 5D-PFD, respectively, which suggested the more polar nature of PFD in the ground state than that of excited state compared with 5D-PFD. Density functional theory (DFT) results demonstrated a significant propensity of ICT from the electron-donor, methyl and carbonyl group to the amine group as an electron donor. The binding of metal ions with PFD or 5D-PFD induced a red-shift of π → π* transition and blue-shift of n → π* transition, respectively, indicating that the pyridone ring showed more stability upon binding of unoccupied orbital of metal ions with lone-pair electron of oxygen atom and thus prompted the electronic distribution on phenyl unit. Upon addition of metal ions, the aromatic region presented the characteristic upfield shifts, and the resonance contributed by 3-H showed a significant downfield chemical shift/deshielding effect, indicating the deduced resonance of 3-H and the improved electron distribution of phenyl unit. The binding and docking of human serum albumin showed that the affinity of 5D-PFD with HSA was lower than that of PFD, and also 5D-PFD might prefer to present free forms in the blood with better efficacy comparing with PFD. The pharmacokinetic of half-time (T1/2) for oral and i.v. administration of 5D-PFD was found around 19 and 30 min, higher than that of i.v. administration of PFD, 8.6 min, reported by Giri et al. The results of this work suggest that the deuteration enhances the metabolism of PFD significantly with little change of physical-chemical property.