Structure-Guided Design of Planarized Catechin Derivatives: Enhancing Antioxidant and Multifaceted Biological Activities for Therapeutic Applications

Oxidative stress is a major driver of chronic disease, making natural polyphenols attractive scaffolds for modulating inflammation, proteostasis, and cell fate. However, green-tea catechins possess a twisted, conformationally flexible flavan-3-ol framework that limits π-conjugation, phenoxyl-radical stabilization, and productive interactions with biological targets. This review presents a structure-based framework in which conformational planarization serves as a strategy for functional amplification. Preorganization of the A/C–B inter-ring bond into a nearly coplanar arrangement reduces the conformational entropy penalty (−TΔS) upon binding or reaction while extending conjugation, strengthening π–π interactions, and facilitating redox reactions. This review highlights planarized catechin (PCat) architectures, including PCat–DTPA (a lesion-activated metal-responsive antioxidant), PCat–TrOH (a self-regenerating antioxidant network), procyanidin B3–PCat hybrids, and a planar silybin analog, illustrating how planarization and multivalent recognition enhance ROS regulation, inhibit amyloid-β aggregation and neurotoxicity, and suppress cancer cell phenotypes. Collectively, these studies establish PCat as a modular platform for the mechanism-informed design of disease-tailored phenolic antioxidants.