Mechanism-resolved structure-activity relationships in flavonoid antioxidants enabled by tail-assisted ESIPT and...

Excited-state intramolecular proton transfer (ESIPT) serves a pivotal function in augmenting the photochemistry and antioxidant characteristics of flavonoid derivatives. Nevertheless, most natural flavonoids are intrinsically ESIPT-inactive. In ESIPT-active systems, the ESIPT process frequently consumes phenolic hydroxyl groups, which constitute the principal reactive loci for radical scavenging. To overcome this limitation, we propose an ingenious design strategy to decouple ESIPT from phenolic hydroxyl consumption and enable dual-mode enhancement of antioxidant activity through introducing a tail-assisted proton transfer pathway based on N-H···N interactions. Experimentally validated antioxidant flavonoids, including butin and 6,7,4'-trihydroxyisoflavone, were selected as models, together with their tail-modified derivatives were all investigated via DFT and TD-DFT calculations. A mechanism-resolved structure-activity relationship (SAR) reveals that folded spatial molecular conformation promotes more efficient intramolecular interactions after tail modification, leading to significantly enhanced antioxidant performance relative to planar counterparts. Notably, this research, for the first time, uncovers the relationship between twisted intramolecular charge transfer and antioxidant activity, revealing its negligible contribution and mechanistic origin. Our study establishes an experimentally grounded, mechanistically resolved SAR framework in which tail-assisted ESIPT and spatially folded conformations cooperatively modulate antioxidant activity, providing practical design blueprint for next generation tail-assisted antioxidant drugs with improved pharmacological potential.