Flavonoids with photoluminescence, a class of organic compounds, exhibit diverse and significant biomedical properties, including anti-inflammatory and antioxidant activities, inhibition of platelet aggregation, reduction of plasma lipoprotein levels and suppression of cellular proliferation [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. In recent years, flavonoid molecules exhibit significant potential in the fields of cancer diagnosis and anticancer drug development [11], [12]. Considerable attention has been directed toward flavonoid based molecules in antioxidant research, primarily due to their unique excited-state intramolecular proton transfer (ESIPT) characteristics [13], [14], [15]. Upon photoexcitation, rapid proton transfer is enabled by this property, resulting in the formation of a stable tautomer [16]. Although studies have shown that after undergoing ESIPT, the molecule's ability to scavenge reactive oxygen species is significantly enhanced, traditional flavonoids still face substantial challenges in clinical translation despite their promising bioactivities [17]. To illustrate, suboptimal bioavailability is attributed to the poor aqueous solubility of these compounds, while the therapeutic efficacy of oral administration is constrained by their limited intestinal absorption [18], [19]. Furthermore, the duration of pharmacological action is curtailed by rapid metabolic degradation and the risk of nonspecific toxicity is heightened by the absence of efficient targeted delivery mechanisms [20], [21]. The translation of flavonoids from basic research to clinical therapy is severely hindered by these inherent limitations. Fortunately, glycosylation offers a promising strategy to ameliorate these constraints, thereby potentiating the pharmacodynamic activity of flavonoids [22]. Currently, all known flavonoid molecules exhibit stronger antioxidant properties after ESIPT (keto⁎ (K⁎) state). In our previous work, we showed that apigenin possesses an ESIPT pathway that proceeds directly from the enol (E) to the K⁎ tautomer without populating an observable enol⁎ (E⁎) state, thereby enabling it to fully exploit the potent antioxidant properties associated with the K⁎ configuration [23]. These findings provide important insights for the structural optimization of flavonoid compounds. Accordingly, a glycosylated flavonoid exhibiting ESIPT with non-existent E⁎ state fluorescence was conceived so that the typical pharmacological drawbacks could be mitigated and the biological activity prolonged. Concomitantly, flavonoids without ESIPT characteristics were also examined to determine how glycosylation influences their antioxidant activity. These considerations underscore the need for a deeper understanding of how glycosylation and ESIPT regulate the antioxidant performance of flavonoid based systems and reveal new mechanistic questions.

In this context, baicalein (exhibiting ESIPT activity) and 6,7,4′-trihydroxyisoflavone (lacking ESIPT activity) and their glycosylated derivatives were selected as model systems in the present study (See Scheme 1). Their ESIPT behavior and antioxidant performance were subsequently subjected to systematic investigation in an aqueous solution environment. Density functional theory (DFT) and time-dependent DFT (TD-DFT) were employed to obtain rigorously optimized geometries. A comprehensive analysis was conducted on key parameters including bond lengths, bond angles, non-covalent interactions, frontier molecular orbital distributions, vibrational spectral characteristics, and potential energy curves. Furthermore, the intrinsic relationship between structural modifications and activity regulation was explored in depth from the perspectives of electronic structure and energy changes. Detailed computational results and mechanistic analyses will be elaborated in subsequent sections.