Pseudo-natural products as next-generation scaffolds: redefining the future of medicinal chemistry

Natural products (NPs) have long provided privileged scaffolds for drug discovery, yet their biosynthetic restrictions limit exploration of broader natural product chemical space. Pseudo-natural products (pseudo-NPs) have emerged as a promising strategy to overcome these limitations by recombining biosynthetically unrelated natural product fragments into unprecedented frameworks. These scaffolds retain NP-inspired features while extending into novel structural and functional space, often leading to bioactivities not achievable with classical derivatives. This review summarizes recent advances in pseudo-NP design, highlighting fragment selection, connectivity principles, cheminformatic evaluation, and the role of phenotypic profiling, particularly the cell painting assay (CPA), in functional annotation and mode-of-action elucidation. Representative scaffolds, including indotropanes, apoxidoles, pyrano-furo-pyridones, and pseudo-rutaecarpines, are discussed in the context of antiproliferative, anti-inflammatory, antibacterial, and autophagy-related activities. While only a few groups worldwide currently explore this field, the collective evidence underscores the translational promise of pseudo-NPs. Future progress will depend on broader scientific engagement, in vivo validation, and the expansion of fragment diversity to inspire the next generation of therapeutic agents.