Synthesis of novel spiroisoxazolidino hybrids of alantolactone and isoalantolactone via 1,3 dipolar nitrone cycloaddition and its antimicrobial Evaluation

Alantolactone and isoalantolactone are two isomeric sesquiterpene lactones that were isolated from Innula recemosa. Here, we are used for the semisynthesis of novel isoxazolidine hybrids of alantolactone and isoalantolactone through a two-step process: nitrone synthesis followed by nitrone 1,3-dipolar cycloaddition. The formation of the cycloadduct was well characterized via modern spectroscopic techniques such as HRMS, ¹H NMR, ¹³C NMR, DEPT-90, DEPT-135, and 2D NMR. This study also includes the synthesis of dinitrone with glyoxal and terephthalaldehyde, which is used for the dinitrone cycloadduct of alantolactone and isoalantolactone. Both nitrone cycloaddition and dinitrone cycloaddition proceed with high regio- and diastereoselectivity, resulting in the formation of only one isomer. The formation of the α-cycloadducts and the absolute configuration were established through 2D NMR and single-crystal X-ray diffraction analysis. The antimicrobial activity of all synthesized compounds was evaluated against a panel of Gram-positive and Gram-negative pathogens. Compounds 3f and 4f exhibited potential antimicrobial activity against drug-sensitive and -resistant Staphylococcus aureus strains, with minimum inhibitory concentrations ranging from 6 to 10 µM. A time-kill kinetics assay suggested that compounds 3f and 4f are bacteriostatic. Furthermore, scanning electron microscopy analysis confirmed that compounds 3f and 4f cause significant morphological alternations and exert potent antibacterial effects by causing substantial cellular damage.