This medicinal chemistry study reports RBG derivatives and identifies compound 2-5c as a more potent Nrf2 activator (EC50 4.18 µM) that is neuroprotective in MPP+-treated BV2 cells and rescues motor deficits in MPTP mice.

Presents a tangible preclinical lead — a small-molecule Nrf2 activator with in vitro and in vivo efficacy in PD models — that targets oxidative stress/neuroinflammation and merits further PK, safety, and translational evaluation.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response and a promising therapeutic target for Parkinson's disease (PD). Resibufogenin (RBG), a bioactive bufadienolide from toad venom, has been identified as a potential Nrf2 agonist; however, its application is limited by cytotoxicity and poor drug-like properties. Herein, we report the rational design, synthesis, and biological evaluation of a series of RBG derivatives modified at the C3, C14-C15, and C17 positions. Systematic structure-activity relationship (SAR) studies identified 2-5c, featuring a C3 2-chloroacryloyl group and a C17 pyrimidine substitution, as a potential Nrf2 activator (EC50 = 4.18 μM), exhibiting approximately 7-fold greater activity than RBG. Importantly, 2-5c demonstrated neuroprotective effects in MPP+-induced BV2 microglial cells and effectively ameliorated motor deficits in an MPTP-induced PD mouse model. These findings suggest that 2-5c represents a promising candidate for further investigation in the development of novel Nrf2-based therapies for PD.