Design, Synthesis, and Biological Evaluation of Pseudo‐Natural Products Inspired by Aryloctahydroindole Alkaloids

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Abstract
We report the design, synthesis, and biological characterization of a pseudo‐NP (PNP) collection inspired by the mesembrine alkaloid scaffold. A scalable, microwave‐assisted intramolecular Diels–Alder furan cyclization enabled efficient access to the 3a‐aryloctahydroindole (AOHI) core, which served as a versatile intermediate for diversification through NP‐fragment fusion. The resulting AOHI‐based PNPs explore chemical space bridging properties of NPs and drug‐like molecules. Morphological and bioenergetic profiling revealed distinct mitochondrial phenotypes, including altered morphological features and respiration consistent with complex I perturbation. These findings highlight the AOHI scaffold as a versatile and synthetically accessible alkaloid‐derived fragment for PNP design and as a valuable source for novel biologically active compound classes.
Funding Information
  • Max-Planck-Gesellschaft
  • Innovative Medicines Initiative
  • Seventh Framework Programme

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