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

## TL;DR

Scientists designed and tested new pseudo-natural compounds based on a specific alkaloid structure, finding they affect mitochondria in unique ways.

## Contribution

A scalable synthesis method for pseudo-natural products based on the mesembrine alkaloid scaffold was developed and biologically evaluated.

## Key findings

- AOHI-based pseudo-natural products show drug-like properties and access new chemical space.
- Compounds induced mitochondrial phenotypes, including morphological changes and respiration inhibition.
- The AOHI scaffold is a synthetically accessible platform for biologically active compound design.

## 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.

Mesembrine alkaloid pseudo‐natural products were synthesized employing a microwave‐assisted Diels–Alder reaction as a key step. Morphological profiling by cell painting revealed compound‐topology‐dependent mitochondrial fragmentation or inhibition of respiration.© 2026 WILEY‐VCH GmbH