Indole is a privileged structural motif in medicinal chemistry, known for its unique bicyclic fusion of benzene and pyrrole rings that confers exceptional electronic and conformational versatility. This enables indole derivatives to mimic peptide structures, form hydrogen bonds, and engage in π–π stacking with protein residues, making them invaluable in targeting a wide array of biological receptors. As a result, indole-containing compounds are prevalent across an expansive range of pharmacological classes not only as anticancer, anti-inflammatory, and antiviral agents but also in cardiovascular, neurodegenerative, metabolic, and antiparasitic therapies, as highlighted by several recent reviews and structure–activity relationship (SAR) studies.[1], [2], [3] Compared with other nitrogen-containing heterocycles, indoles demonstrate a higher frequency of clinical translation. A comprehensive review published in 2024 revealed that indole-based drugs have outpaced other azaheterocycles in FDA approvals over the past decade, underlining their exceptional success as pharmacophores in modern drug development.4

The synthetic adaptability of the indole core, allowing substitution at nearly all positions on the ring, has enabled medicinal chemists to fine-tune their physicochemical and pharmacokinetic properties, making them suitable for both small molecule drugs and hybrid therapeutic designs. Despite these advances, the clinical journey of indole-based drugs has also included setbacks. Several FDA-approved indole derivatives have recently been withdrawn from the market because of concerns related to long-term safety or insufficient efficacy in confirmatory trials. Conversely, others are being explored for new therapeutic applications beyond their original indications, highlighting both the challenges and opportunities associated with this scaffold. These developments reflect the evolving regulatory landscape and the need for continuous safety re-evaluation of existing drugs, especially those approved before the current standards of pharmacovigilance.

This review aims to provide a comprehensive analysis of FDA-approved, withdrawn, and investigational indole-based drugs over the last decade. In doing so, we address key questions: What drove their approvals? Why were some compounds withdrawn? In which therapeutic classes are indoles gaining momentum? Which biological targets remain underexplored despite promising early leads? Moreover, we examine the growing trend of repurposing indole drugs for multi-target applications and evaluate the clinical strategies used to reassess safety and efficacy, particularly in light of recent late-stage failures. By integrating chemical structure, pharmacology, and regulatory data, this review identifies research gaps, highlights therapeutic opportunities, and outlines scaffold optimization strategies for future indole-based drug design.

Ultimately, this work offers the research community an evidence-based roadmap to guide safer development, strategic repurposing, and more targeted innovation within the indole pharmacophore space.