Strategic approaches to the discovery of biologically active indole derivatives: a comprehensive review

Indole, an aromatic heterocyclic compound formed by the fusion of a benzene ring with a pyrrole ring, is widely distributed in the secondary metabolites of plants, animals, and marine organisms. Owing to its unique physicochemical properties and high structural modifiability, indole derivatives can engage in specific interactions with various biological targets, demonstrating a broad spectrum of bioactivities including anticancer, anti-inflammatory, antiviral, and antibacterial effects. Consequently, indole holds an indispensable position in innovative drug discovery and development. This review provides a comprehensive summary of the primary strategies employed in the discovery of indole derivatives. These encompass structure optimization approaches inspired by natural products, such as structure simplification, diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS), the "pseudo-natural product" (PNP) strategy, and bioinspired synthesis based on biosynthetic building blocks. Additionally, strategies like scaffold hopping, molecular hybridization, drug repurposing, and multicomponent reactions (MCRs) for constructing indole-based molecules are discussed. Particular emphasis is placed on target structure-based discovery strategies for indole derivatives, including ligand-based structure modification, molecular docking-assisted high-throughput virtual screening, and fragment-based drug design (FBDD). Furthermore, the application of emerging techniques such as phenotypic screening, DNA-encoded library (DEL) technology, and free energy perturbation (FEP) calculations in indole-based drug research and development is highlighted. This review aims to systematically organize the multi-dimensional R&D framework for indole derivatives, analyze the specific value of each strategy in addressing drug discovery challenges, and provide a theoretical foundation and methodological support for the rational design and development of novel indole-based drugs. It is anticipated that this work will further enhance the efficiency and innovation level in the development of this class of compounds.