Caffeine-derived 8-α-methylthioglycolic acid compounds as promising neuroprotective agents in cellular models of neurotoxicity

The effects of a series of caffeine-8-α-methylthioglycolic acid derivatives (Jas 1–Jas 10), possessing potential applicability in neurodegenerative diseases, were investigated using neurotoxicity models based on the human neuroblastoma cell line SH-SY5Y. These compounds contain various substituents that modify and improve the physicochemical properties of caffeine, including solubility, molecular weight, and acidity, which may influence their biological activity. The proposed mechanism of action is associated with the modulation of G protein-coupled adenosine receptors in neuronal cells. The neuroprotective potential of the compounds was evaluated in an L-glutamate (L-GLU, 60 mM, 24 h)-induced excitotoxicity model and hydrogen peroxide (H 2 O 2 , 5 μM and 6 μM, 1 h)-induced oxidative stress models. Cell viability and intracellular reactive oxygen species (ROS) production were analyzed using standard in vitro assays. The results demonstrated that the tested derivatives exhibited antioxidant and moderate neuroprotective effects in both experimental models. The most pronounced activity was observed for compound Jas 9 in the L-GLU-induced neurotoxicity model and for compound Jas 8 in the H 2 O 2 -induced oxidative stress model. Furthermore, Jas 8 statistically significantly reduced intracellular ROS production (+++ p < 0.001), supporting its strong antioxidant potential. Overall, these findings indicate that the selected caffeine derivatives are promising candidates for further pharmacological and toxicological evaluation.