Advances in Naturally and Synthetically Derived Bioactive Sesquiterpenes and Their Derivatives: Applications in Targeting Cancer and Neurodegenerative Diseases

Sesquiterpenes are a diverse class of natural products that have garnered considerable interest for their potent bioactivity and structural variability. This review highlights advances in the derivatization of various sesquiterpene lactones, quinones, and alcohols, particularly in targeting cancer and neurodegenerative diseases. The structural modifications discussed include the incorporation of triazole, arylidene, or thiol moieties with eudesmane, guaiane, and germacranolide-type sesquiterpenes, among others. In addition, the conjugation with chemotherapeutics, as well as the development of nanoscale therapeutics, is also discussed. Such modifications have expanded the pharmacological potential, enabling improved specificity, cytotoxicity profiles, and sensitization toward tumor cells. Additionally, sesquiterpenes such as parthenolide (20), pterosinsade A (176), and cedrol (186) have demonstrated potential in mitigating neurodegeneration via anti-inflammatory and antioxidant signaling pathway-modulation mechanisms, with potential applications in Alzheimer’s, Parkinson’s, and ALS diseases. Mechanistic insights into redox signaling modulation, NF-κB inhibition, ROS regulation, and disruption of aggregation underscore their multifaceted modes of action. This review highlights the translational promise of sesquiterpene derivatives as dual-action agents for potential drug development in a plethora of diseases that are caused by inflammation and free-radical damage. It provides a framework for future rational design of multifunctional drug candidates and therapeutics.