DNA-compatible synthesis of amidine pharmacophores via late-stage amine modification

Abstract

Amidines are prevalent pharmacophores that are widely utilized in medicinal chemistry. Selective modification of amines within DNA-encoded libraries (DELs) offers a direct approach for constructing these pharmacophores, thereby enhancing library structural diversity. Herein, we report a hydroxylamine-mediated conversion of amino groups to amidines based on our ongoing development of in situ conversion strategies. This method enables efficient coupling with diverse nitriles and demonstrates broad tolerance to protecting groups. Furthermore, we successfully applied this approach for the on-DNA synthesis of iNOS and PAD4 inhibitors.