A complexity-to-diversity strategy for andrographolide derivatization and discovery of potential antiviral and anticancer scaffolds.

Structurally intricate natural products serve as valuable scaffolds in drug discovery, yet efficient strategies to diversify their core frameworks into novel chemical entities remain a significant challenge. Herein, we present a complexity-to-diversity (CtD) strategy for the derivatization of andrographolide by integrating visible light-induced aziridination with subsequent transformations. This methodology enables the synthesis of aziridine-functionalized andrographolide derivatives, which are readily transformed into spiro-imidazoline architectures and amino-substituted tricyclic systems, generating a diverse array of nitrogen-enriched complex molecules. Notably, biological evaluation identified several leads that surpass the parent andrographolide: anti-SARS-CoV-2 potency reached EC50 = 2.8 μM, while inhibitory activity against nasopharyngeal carcinoma (C666) reached EC50 = 5.4 μM. This CtD strategy provides rapid, rational access to drug-like chemical space previously inaccessible from terpenoid feedstocks.