Pseudo‐Natural Products Inspired by Aspidospermidine‐, Strychnos‐, and Koumine Monoterpene Indole Alkaloids Reveal Pyrimidine Biosynthesis Inhibitors

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In pseudo‐natural product (PNP) design, natural product fragments are combined in arrangements not found in nature to afford novel biologically relevant NP‐related compound classes. A pseudo‐natural product compound collection inspired by aspidospermidine‐, strychnos‐, and koumine monoterpene alkaloids was designed and rapidly synthesized to afford a collection of 78 compounds representing eight structurally different PNP classes. Evaluation of the collection for biological relevance by means of the cell painting assay, including a recently reported subprofile analysis, revealed that one of the structural classes is enriched in and defines a new chemotype of de novo pyrimidine biosynthesis inhibitors. Our results exemplify the combination of pseudo‐natural product design and unbiased morphological screening technologies as an efficient means to rapidly access and identify novel biologically relevant chemotypes.