Molecular Editing of Bilobalide: Expanding Chemical Space and Biological Opportunities

Abstract Complex natural products often show promising biological activity but suffer from liabilities, such as chemical or metabolic instability, that can limit their therapeutic evaluation. This perspective highlights bilobalide as a case study for how targeted molecular editing can transform a fragile, structurally dense natural product into a platform for biological discovery and medicinal chemistry. Bilobalide, a neuroprotective and anti-inflammatory sesquiterpene trilactone from Ginkgo biloba, features a fragile core that has historically hindered comprehensive structure–activity relationship studies. We trace the evolution of bilobalide chemistry from early, scaffold-degrading modifications to modern late-stage molecular editing. By utilizing activated iso-bilobalide intermediates, recent synthetic strategies have achieved a precise lactone-to-lactam (O-to-N) core atom exchange. This structural modification significantly improves chemical stability and eliminates native GABAA receptor antagonism. Subsequent diversification generated the first antiferroptotic bilobalide analogues, while proteomic profiling via CETSA-MS nominated prolyl endopeptidase (PREP) as a target driving their antineuroinflammatory activity. Editing the bilobalide framework illustrates how late-stage molecular editing can repurpose complex, unstable natural products into therapeutic starting points with known molecular targets.