From bench chemistry to clinical candidates: pharmacological profiles, position-specific SARs, and patent landscape of pyridone derivatives (2014-2025).

Pyridone-based heterocycles, encompassing both 2-pyridone and 4-pyridone frameworks, represent a clinically validated class of privileged scaffolds with broad pharmacological relevance, as evidenced by their incorporation into multiple approved drugs and emerging clinical candidates across diverse therapeutic areas. Although numerous reviews have addressed specific biological activities or synthetic aspects of pyridone chemistry, a unified scaffold-position structure-activity relationship (SAR) framework integrating pharmacological outcomes across multiple therapeutic classes has remained largely unavailable. This review systematically examines the medicinal chemistry and pharmacological landscape of pyridone derivatives reported between 2014 and 2025. Particular emphasis is placed on the critical evaluation of SARs within individual therapeutic classes, highlighting how substitutions at key scaffold positions, such as N-1, C-3, C-4, and C-5, and peripheral aryl sites influence biological activity. The analysis reveals recurring substitution patterns that govern potency, selectivity, and therapeutic outcomes, guiding rational pyridone-based drug design. Drawing upon SAR trends across anticancer, antidiabetic, antihypertensive, antimalarial, anti-inflammatory, antibacterial, antifungal, antiviral, cardiovascular, and central nervous system (CNS) applications, as well as recent emerging targets, the review further consolidates these findings into a generalized position-guided framework for rational optimization of the pyridone scaffold. In parallel, FDA-approved pyridone-containing drugs, clinical candidates, and recently disclosed patented scaffolds are critically evaluated to provide translational insights that link advances in medicinal chemistry to therapeutic development. Collectively, this review offers a comprehensive reference and practical roadmap for the discovery and optimization of next-generation pyridone-based therapeutics across a broad spectrum of pharmacological targets.