Diversity-oriented semi-synthesis of Alantolactone and Isoalantolactone hybrids employing azomethine ylide cycloaddition pathway

Alantolactone and isoalantolactone, naturally occurring sesquiterpene lactones, are known for their significant pharmacological properties, including anti-inflammatory, anticancer, and antimicrobial activities. However, their biological potential can be further enhanced by structural modification. In this study, we report a diversity-oriented semi-synthesis of novel alantolactone and isoalantolactone hybrids through an azomethine ylide cycloaddition pathway. This efficient process allowed us to create complex and diverse molecular structures. Specifically, we focused on modifying the, α, β-unsaturated exocyclic double bond from butyrolactone core to produce dispirohybrids, including compounds like dispirooxindolo, indanedione, and acenaphthylen-2-one, using amino acids and diketones. The synthesized hybrids were fully characterized using various spectroscopic techniques (1D, 2D-NMR, HRMS, and X-ray diffraction). In silico studies revealed favorable drug-like properties for the synthesized spirocompounds, including ideal physicochemical characteristics, promising pharmacokinetic behavior, excellent oral bioavailability, and minimal toxicity risk. These predictions highlight the potential of these spiroderivatives as strong candidates for further development in drug discovery. This work shows that the azomethine ylide cycloaddition is a useful method for enhancing the chemical and biological diversity of natural products.