Green mechanochemical synthesis of thiazolyl–hydrazone phenolic derivatives and evaluation of their antioxidant activity

Oxidative stress plays a pivotal role in the onset and progression of several chronic diseases, prompting the search for novel antioxidant agents. In this context, hydrazone and thiazole scaffolds are particularly attractive due to their ability to stabilize radical intermediates. In the present study, a series of phenolic thiazolyl–hydrazone derivatives was synthesized using a straightforward and sustainable approach. Alongside a conventional solution-phase protocol, a one-pot mechanochemical telescoped strategy was developed for the first time, operating at room temperature with ethanol as a liquid-assisted grinding additive (LAG). The environmental efficiency of both methodologies was evaluated using green metrics, including SPR, PMI, E -factor and RME. The mechanochemical approach dramatically reduced solvent consumption (up to 99%), improved the PMI from 35.3 to 2.05, and lowered the E -factor from 34.3 to 1.05, while simultaneously increasing overall yields, as observed for ES3 (from 42% to 80%). Antioxidant activity was evaluated using DPPH and ABTS radical-scavenging assays with ascorbic acid as the reference standard. From a biological point of view, electron-rich derivatives exhibited the highest antiradical activity: In particular, the catechol-containing compounds ES26 and ES27 emerged as the most potent derivatives of the series, while ES9, ES16, and ES17 also displayed a favorable antioxidant profile. Notably, the latter compounds outperformed ascorbic acid. Structure–activity relationship analysis highlighted the key role of 3,4-dihydroxy and 3,4-dimethoxy substitution patterns in enhancing radical-scavenging efficiency. Overall, the one-pot mechanochemical sequence represents a rapid, solvent-minimized, energy-efficient and waste-reduced route to phenolic thiazolyl–hydrazone derivatives, enabling access to new compounds with antioxidant activity higher than the reference standard and laying the foundation for future mechanistic and biological investigations.