Natural Product-Inspired Bioactive Analogues: Design, Synthesis, and Structure–Activity Relationships

Natural products have long been one of the most prolific sources of biologically relevant molecular scaffolds, providing the foundation for a remarkable share of approved drugs. Their structural diversity, three-dimensional complexity, and evolutionary optimisation for binding biological targets continue to make them a privileged starting point for the discovery of new bioactive compounds.Despite the central role of natural products in drug discovery, translating natural scaffolds into clinically viable molecules remains challenging. Many bioactive natural products suffer from low isolation yields, complex synthetic routes, poor pharmacokinetic profiles, or off-target effects. The rational design and synthesis of analogues offer a powerful strategy to address these limitations, enabling the optimisation of potency, selectivity, and physicochemical properties while retaining the biological relevance of the parent scaffold.This Research Topic aims to bring together contributions focused on the design, synthesis, and biological evaluation of bioactive analogues derived from, or inspired by, natural products. Particular emphasis is placed on studies in which molecular modification is directly connected to a measurable biological function, providing meaningful structure–activity insights. Unlike Research Topics centred on isolation or natural product discovery, this collection focuses on designed and semisynthetic analogues with clear SAR data. We welcome work spanning total synthesis, semisynthesis, library construction, and computational design, as well as studies that integrate synthetic chemistry with biological, pharmacological, or mechanistic evaluation. Together, these contributions will help shape a clearer understanding of how natural product-inspired chemistry can deliver safer, more effective, and more sustainable bioactive molecules.We welcome Original Research, Review, Mini Review and Perspective articles on themes including, but not limited to:o Design and synthesis of natural product-inspired bioactive analogueso Semisynthetic modification of natural scaffolds for improved bioactivityo Construction and screening of analogue libraries from bioactive natural productso Structure–activity relationship studies of natural product-derived compoundso Optimisation of potency, selectivity, and physicochemical propertieso Computational and AI-guided design of natural product analogueso Total synthesis enabling access to novel bioactive scaffoldso Mechanistic and target identification studies of bioactive analogueso Mechanistic and target identification studies of bioactive analogues Topic editors: Jesús García Zorrilla, Marco Masi, Nuno Manuel Xavier Source: https://www.frontiersin.org/research-topics/82540/natural-product-inspired-bioactive-analogues-design-synthesis-and-structure-activity-relationships