Microwave-assisted synthesis of 3,5-disubstituted isoxazoles and evaluation of their anti-ageing activity

• Green, one-pot mw assisted, regioselective synthesis of 3,5-disubstituted isoxazoles.
• Short reaction times of the uncatalysed reactions, compared to conventional methods.
• Evaluation of cytoprotective and anti-ageing activity in vitro and in vivo.
• Chroman analogue 17, was the most active compound at cellular and organismal level.

One-pot uncatalysed microwave-assisted 1,3-dipolar cycloaddition reactions between in situ generated nitrile oxides and alkynes bearing protected antioxidant substituents, were regioselectively afforded 3,5-disubstituted isoxazoles. The yields were moderate, based on the starting aldehydes, while the reaction times were in general shorter than those reported in the literature.The cytoprotective and anti-ageing effect of the final deprotected compounds was evaluated in vitro, on cellular survival following oxidative challenge and in vivo, on organismal longevity using the nematode Caenorhabditis elegans. The activity of the isoxazole analogues depends on the nature and the number of the antioxidant substituents. Analogue 17 bearing a phenolic group and a 6-OH-chroman group is a promising anti-ageing agent, since it increased survival of human primary fibroblasts following treatment with H2O2 and extended C. elegans lifespan.

Figure optionsDownload as PowerPoint slide