Synthetic flavonoid dimers: Synthesis strategies and biological activities

The continuous search for novel and safer drug candidates remains imperative to address ever-evolving health challenges. Nature has long served as a source of inspiration for drug discovery, particularly through bioactive compounds such as flavonoids. Among them, flavonoid dimers, first identified nearly a century ago, have shown promising biological activities that often surpass those of their monomeric counterparts while showing minimal side effects. Nonetheless, these compounds suffer from limitations such as low bioavailability and moderate potency. To mitigate these challenges, researchers have developed synthetic strategies to obtain them, expand their structural diversity, and optimize their properties. The design of completely unnatural flavonoid dimers offers new opportunities for drug discovery. In contrast to previous review articles, this review explores the potential of synthetic flavonoid dimers. It provides an overview of the main synthetic methodologies to obtain them, illustrating how the evolution of the synthetic protocols has also driven the development of novel unnatural compounds. It then focuses on highlighting the bioactivities reported for synthetic flavonoid dimers, in particular anti-inflammatory, anticancer, and antimicrobial. Finally, this review highlights a specific subclass of synthetic flavonoid dimers that emerged in the last decade but remains underexplored, proposing its classification as fused bis-flavonoids . The aim is to drawattention to their potential importance by giving them a unique nomenclature from other subclasses and highlighting their biological activities. • Flavonoid dimers are flavonoid derivatives with acknowledged biological potential. • Synthetic flavonoid dimers offer an opportunity to improve upon the natural derivatives. • Synthetic strategies to yield dimers focus on several cross-coupling reactions. • Several synthetic flavonoid dimers have shown good potential as anti-inflammatory agents and regulators of drug resistance. • Extended linker moieties and tunable polarities are features that favor synthetic derivatives over natural dimers.