Remarkable diversity of alkaloid scaffolds in Piper fimbriulatum

The Piperaceae plant family is known for its special phytochemistry and is widely recognized as a rich source of bioactive natural products. Piperaceae plants, especially from the Piper genus, have been extensively investigated in the past decades; yet, new alkaloids are still regularly reported from this genus. Here, we investigated the alkaloid diversity of Piper fimbriulatum using a metabolomics workflow that combines untargeted LC-MS/MS analysis with a range of recently developed computational tools. In particular, we leverage open libraries of MS/MS spectra and metabolomics data repositories for metabolite annotation and to direct isolation efforts towards structurally-novel compounds (i.e., dereplication). We identified several alkaloids belonging to 5 different classes and isolated one novel seco - benzylisoquinoline alkaloid with a linear quaternary amine nitrogen. Notably, many of the identified compounds were never reported in Piperaceae plants. Our findings expand the known alkaloid diversity of the Piperaceae family, and demonstrate the potential of revisiting well-studied plant families using state-of-the-art computational metabolomics workflows to uncover previously overlooked chemodiversity. Finally, we contextualized our findings in a broader evolutionary framework by mapping literature reports for the identified alkaloid scaffolds onto the angiosperm tree of life, which highlighted the remarkable alkaloid diversity in the Piper genus.