Excited-state antioxidant activity for apigenin based on external electric field-modulated ESIPT behavior: TD-DFT and molecular docking calculations

Apigenin (Api), a flavonoid possessing dual features of antioxidant activity and intramolecular hydrogen bond (IMHB), is subjected to an external electric field (EEF) to investigate its excited-state antioxidant activity after excited state intramolecular proton transfer (ESIPT) behavior employing the density functional theory (DFT) and time-dependent DFT (TD-DFT) methods, as well as molecular docking. The existence of IMHB is demonstrated by structural parameters and AIM topological analysis, where Api in the enol^⁎ form under an EEF of +60 × 10⁻⁴ a.u. possesses strong IMHB. The potential energy curves confirm that the ESIPT process varies from barrierless to barriered as the positive EEF grows, thus determining the excited-state form. Api exhibits strong excited-state antioxidant activity in vitro whether or not under an EEF, especially under the EEF of −40 × 10⁻⁴ a.u., utilizing HOMO energy. According to average local ionization energy (ALIE), the electrophilic reaction site also changes after ESIPT process under the EEF, and the activity is significantly increased. Furthermore, activation of the antioxidant Keap1-Nrf2-ARE pathway in vivo, namely, the interaction of Keap1 protein with Api, calculated by molecular docking, suggests that an interaction between the Keap1 and excited-state Api exists accompanying lower and variable bind energy under the distinct EEFs. Taken together, combining the modulation of the ESIPT process with the excited-state antioxidant activity is an effective approach to enhance the antioxidant activity of compounds.