Mechanochemical Synthesis and Antioxidant Activity of Curcumin‐Templated Azoles

A solvent‐free, mechanochemical method for the synthesis of curcumin ( 1 ) derived 3,5‐bis(styryl)pyrazoles and 3,5‐bis(styryl)isoxazole ( 2a–g ) at room temperature, with very short reaction time, is reported. Such earlier structural modifications of curcumin, at its β‐diketone unit by transforming it into an isosteric pyrazole or isoxazole unit, required prolonged heating. The evaluation of the antioxidant activity of these compounds, based on DPPH, FRAP, and β‐carotene bleaching assays, showed that several of these azoles are better antioxidants than curcumin, with the isoxazole derivative 2g being overall the best. Typically, the inhibition of 2,2‐diphenyl‐1‐picrylhydrazyl (10 −2 mmol), expressed as EC 50 values, by curcumin ( 1 ), 3,5‐bis(4‐hydroxy‐3‐methoxystyryl)pyrazole ( 2a ), and 3,5‐bis(4‐hydroxy‐3‐methoxystyryl)isoxazole ( 2g ) are 40 ± 0.06, 14 ± 0.18, and 8 ± 0.11 μmol, respectively. Moreover, the reported method is useful in accessing 3,5‐bis(4‐hydroxy‐3‐methoxystyryl)‐1‐phenylpyrazole ( 2b ), which is important in studies related to neuroprotection and Alzheimer's disease, and 2a and 2g , which are inhibitors of protein kinases involved in neuronal excitotoxicity.