Recent advances in the design, development and therapeutic targets of chrysin derivatives

The natural flavonoid chrysin exhibits broad-spectrum bioactivity. However, its clinical utility is severely constrained by suboptimal potency and unfavorable pharmacokinetic properties. Rational chemical modifications, including site-specific derivatization, molecular hybridization, and metal complexation, have yielded numerous chrysin derivatives with enhanced activity and selectivity. These derivatives engage diverse molecular targets, demonstrating considerable potential in various therapeutic areas, including anti-tumor, anti‑inflammatory, anti-diabetic, neuroprotective, and antimicrobial applications. This review systematically summarizes key site‑based modification strategies for chrysin, categorizes and discusses the derivatives according to their target profiles, and provides a detailed analysis of the design, bioactivity, and mechanisms of action of compounds targeting critical proteins such as epidermal growth factor receptor (EGFR), topoisomerase II (Topo II), poly (ADP-ribose) polymerase 1 (PARP1), cyclooxygenase-2 (COX-2), β-ketoacyl-acyl carrier protein synthase III (FabH), α-glucosidase, peroxisome proliferator-activated receptor γ (PPARγ) and cholinesterases (ChE). Recent advances in multi‑target derivatives and metal complexes are also highlighted. Finally, current challenges and future directions are discussed, emphasizing the role of target‑driven design and emerging technologies in guiding the development of next‑generation chrysin‑based therapeutics.