Abstract
<jats:p>Heterocyclic scaffolds are crucial architectures in life sciences. In particular, quinoline and quinazoline frameworks are prominently found in pharmaceutically relevant compounds due to their high bioactivities. Molecular skeletal editing has emerged as a powerful strategy for remodeling complex scaffolds without de novo synthesis, yet controlled substituent migration on these heteroaromatic systems remains largely unexplored. Here, we report an “aryl-to-alkyl” amide migration in quinoline and quinazoline derivatives, enabling intramolecular transposition of an in situ formed amide substituent. Mechanistic studies, including density functional theory (DFT) calculations, reveal that this transformation does not proceed through a conventional Truce–Smiles mechanism, but instead follows a distinct pathway, establishing a new mechanistic paradigm for intramolecular amide migration on heterocyclic frameworks. This work establishes a previously unrecognized mode of skeletal reorganization, expands the scope of functional group rearrangements on heteroaromatic systems, and provides an efficient synthetic route to structurally diverse, biologically relevant quinoline- and quinazoline-based compounds. The rearranged scaffolds were readily converted into PROTACs, with the lead compound displaying potent anti-HCMV activity (EC50 = 0.32 ± 0.14 µM) without detectable cytotoxicity (CC50 > 100 µM). Consistent with genuine PROTAC-mediated degradation of CDK8, these findings highlight the potential of this strategy to enable host-directed antiviral drug discovery.</jats:p>