In natural products (NPs) research, methods for the efficient prioritization of natural extracts (NEs) are key for discovering novel bioactive NPs. In this study a biodiverse collection of 1,600 NEs, previously analyzed by UHPLC-HRMS ² metabolite profiling was screened for Wnt pathway regulation. The results of the biological screening drove the selection of a subset of 30 non-toxic NEs with an inhibitory IC ₅₀ ≤ 5 μ g/mL. To increase the chance of finding structurally novel bioactive NPs, Inventa , a computational tool for automated scoring of NEs based on structural novelty was used to mine the HRMS ² analysis and dereplication results. After this, four out of the 30 bioactive NEs were shortlisted by this approach. The most promising sample was the ethyl acetate extract of the leaves of Hymenocardia punctata (Phyllanthaceae). Further phytochemical investigations of this species resulted in the isolation of three known prenylated flavones ( 3 , 5 , 7 ) and ten novel bicyclo[3.3.1]non-3-ene-2,9-diones ( 1 , 2 , 4 , 6 , 8 – 13 ), named Hymenotamayonins . Assessment of the Wnt inhibitory activity of these compounds revealed that two prenylated flavones and three novel bicyclic compounds showed interesting activity without apparent cytotoxicity. This study highlights the potential of combining Inventa ’s structural novelty scores with biological screening results to effectively discover novel bioactive NPs in large NE collections.