Synthesis and neuroprotective effects of novel chalcone-triazole hybrids

The development of novel neuroprotective agents is urgently needed for the treatment of neurodegenerative diseases, affecting aging individuals worldwide. In this study, a new set of chalcone-triazole hybrids (6a-g) was synthesized and evaluated for their biological properties including cytotoxicity, antioxidant, anti-apoptosis, and neuroprotection using SH-SY5Y cells. The results showed that 6a and 6e provided neuroprotection in oxidative stress-induced neuronal cell damage. Both compounds significantly improved the morphology of neurons and obviously increased cell survival rate of neuronal cells induced by oxidative stress. Additionally, 6a and 6e counteracted H₂O₂‑induced mitochondrial dysfunction, which was supported by maintaining mitochondrial membrane potential, attenuating BAX protein, and increasing BCL‑2 protein within the mitochondria as well as upregulating SOD2 mitochondrial antioxidant enzyme. Interestingly, these compounds promoted neuroprotection via SIRT-FOXO3a signaling pathway similar to resveratrol. The data indicated that the chalcone-triazole derivatives (6a and 6e) could be considered to be promising compounds toward the discovery of disease-modifying candidates for a neurodegenerative therapy.