Therapeutic Applications of Coumarins; Recent Advances and Clinical Limitations: A Systematic Review
TL;DR
Structural relationship analysis reveals that hydroxyl/methoxy substitutions at positions 6 and 7 enhance antioxidant and neuroprotective properties, while 4-aryl groups improve anticancer activity, yet safety, bioavailability, and specificity remain major barriers to clinical translation.
Abstract
Background: Coumarins are benzopyrone compounds found in over 150 plant species, including cinnamon and citrus fruits, which exhibit diverse pharmacological activities. Despite extensive preclinical evidence, their clinical translation remains constrained by toxicity concerns and poor pharmacokinetic profiles. Methods: A systematic literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, ScienceDirect, and Google Scholar for publications from January 2000 to August 2024. Studies reporting therapeutic applications, mechanisms of action, and clinical limitations of coumarins were included, following PRISMA guidelines. Data were extracted on structural features, pharmacological outcomes, and documented toxicities, with qualitative synthesis performed. Results: Coumarins demonstrate therapeutic potential as anticoagulants (warfarin, dicumarol), anticancer agents (daphnetin), anti-inflammatory compounds (esculetin, scopoletin), antioxidants, antimicrobials, neuroprotective agents, and anti-diabetic compounds. Their mechanisms include enzyme inhibition (MAO, PDE, vitamin K epoxide reductase, carbonic anhydrase), signaling pathway modulation (PI3K/Akt/mTOR, Keap1/Nrf2/ARE), and protein interactions (p53). Structure-activity relationship analysis reveals that hydroxyl/methoxy substitutions at positions 6 and 7 enhance antioxidant and neuroprotective properties, while 4-aryl groups improve anticancer activity. However, clinical application is limited by hepatotoxicity (psoralen-induced CYP-mediated oxidative stress), phototoxicity (furanocoumarins under UVA), drug interactions (CYP3A4 inhibition), and poor bioavailability. Conclusion: Coumarins constitute a promising compound class with broad pharmacological actions, yet safety, bioavailability, and specificity remain major barriers to clinical translation. Future directions should focus on rational structural modification, nanotechnology-based delivery systems (liposomes, polymeric nanoparticles), multi-target hybrids, and rigorous human clinical trials to confirm therapeutic efficacy and safety profiles.