Lactone-to-Lactam Editing Alters the Pharmacology of Bilobalide

Precise transformations of natural products (NPs) can fine-tune their physicochemical properties while preserving inherently complex and evolutionarily optimized parent scaffolds. Here, we report an unprecedented lactone-to-lactam transformation on bilobalide, thus improving its stability and paving the way for biological exploration of previously inaccessible chemical space that is highly representative of the parent structure. This late-stage molecular editing of bilobalide enables facile access to a unique library of lactam analogues with altered pharmacology. Through phenotypic screening, we identify