Design, Synthesis, and Phenotypic Profiling of Pyrano-Furo-Pyridone Pseudo Natural Products.

Natural products (NPs) inspire the design and synthesis of novel biologically relevant chemical matter, for instance through biology-oriented synthesis (BIOS). However, BIOS is limited by the partial coverage of NP-like chemical space by the guiding NPs. The design and synthesis of "pseudo NPs" overcomes these limitations by combining NP-inspired strategies with fragment-based compound design through de novo combination of NP-derived fragments to unprecedented compound classes not accessible through biosynthesis. We describe the development and biological evaluation of pyrano-furo-pyridone (PFP) pseudo NPs, which combine pyridone- and dihydropyran NP fragments in three isomeric arrangements. Cheminformatic analysis indicates that the PFPs reside in an area of NP-like chemical space not covered by existing NPs but rather by drugs and related compounds. Phenotypic profiling in a target-agnostic "cell painting" assay revealed that PFPs induce formation of reactive oxygen species and are structurally novel inhibitors of mitochondrial complex I.