From curcumin to structurally diversified analogs: Bioactivities, structure-activity relationships, and molecular...

Curcumin, a natural polyphenolic compound extracted from the rhizome of Curcuma longa, has emerged as a research hotspot in medicinal chemistry owing to its unique diarylheptadienone skeleton (C6-C7-C6), broad-spectrum bioactivities, and multi-target mode of action. However, its inherent drawbacks, including poor water solubility, low in vivo stability, and rapid metabolic rate, have severely hindered its clinical translation and application. In recent years, breakthrough progress has been made in the structural modification and scaffold reconstruction of the curcumin nucleus. Through diverse strategies including monocarbonyl modification, heterocyclic fusion, metal coordination, halogen substitution, and pharmacophore hybridization, a series of derivatives with improved druggability and enhanced bioactivity have been successfully developed. This review systematically collates relevant research literature from 2020 to April 2026, summarizes the latest research advances of curcuminoids in core fields including anticancer, antibacterial, antiviral, anti-inflammatory, antioxidant, and neuroprotective activities by bioactivity classification, and focuses on the structural characteristics, activity advantages, structure-activity relationships (SARs), and molecular mechanisms of representative derivatives. Furthermore, key SAR insights, including the modification of the β-diketone group, regulation of aromatic ring substituents, and the synergy of scaffold fusion with metal coordination, are further refined, and future research directions are prospected. This review aims to provide systematic SAR guidance and insights for the rational design of innovative drugs based on the curcumin scaffold.