Structural Modification of Sesquiterpene Lactones via Michael Addition: Improved Bioactivity and Pharmacokinetics

Sesquiterpene lactones (SLs) are privileged medicinal scaffolds, offering potent bioactivities driven by their reactive α-methylene-γ-lactone motif. This review highlights the literature published up to the first half of 2026, detailing the synthetic methodologies utilized to optimize SLs via Michael addition. We critically evaluate how these structural transformations translate into biological and pharmacokinetic improvements. Specifically, the resulting Michael adducts achieve significantly enhanced solubility in aqueous media and highly refined drug–target interactions. Addressing a clear literature gap unaddressed since earlier foundational reviews, this focus review highlights the literature published up to the first half of 2026. By explicitly correlating synthetic strategies with pharmacological outcomes, such as enhanced efficacy and target specificity, this review provides medicinal chemists with a robust framework to accelerate the development of next-generation SL-based therapeutics.