STRUCTURE–ACTIVITY RELATIONSHIPS AND MECHANISTIC INSIGHTS OF RACETAM DERIVATIVES IN EPILEPSY MANAGEMENT

Epilepsy continues to affect millions globally, and despite advances in treatment, many patients still struggle with drug-resistant forms of the disorder. Among the newer therapeutic options, racetam derivatives have garnered attention for their distinctive mechanism of action—modulating synaptic vesicle protein 2A (SV2A)—which distinguishes them from traditional antiepileptic drugs (AEDs). This review provides a closer examination of the structure–activity relationships (SAR) of racetam analogues, investigating how chemical modifications, such as aromatic substitution, halogenation, and alkyl chain extension, can significantly enhance key properties, including lipophilicity, blood–brain barrier penetration, metabolic stability, and receptor binding. By comparing well-known agents like piracetam and levetiracetam with newer, more refined molecules such as brivaracetam and seletracetam, we highlight the steady evolution in potency, selectivity, and pharmacokinetics. We also explore emerging strategies that aim to address current challenges in drug delivery and tolerability, ranging from stereochemical optimization to nanotechnology-based formulations and prodrug design. Recent findings from both preclinical and clinical studies (2021–2024) underscore the growing relevance of racetams in epilepsy care, highlighting the need for continued innovation in medicinal chemistry and translational research. Ultimately, racetam derivatives represent a compelling intersection of pharmaceutical design and neuropharmacology, offering a promising roadmap for the development of next-generation AEDs tailored to individual patient needs.