Attenuation of 6‑OHDA-Induced Neurotoxicity by 1,2,3-Triazole-Based Sulfonamides through SIRT1 Activity

Due to the irreversible destructive nature of Parkinson's disease (PD), the development of neuroprotective agents is crucially needed as its current medications are only symptomatic treatments. 1,2,3-Triazole is an attractive scaffold for the discovery of novel therapeutic agents due to its versatile biological activities. This study aimed to investigate the neuroprotective effect of 1,2,3-triazole-based sulfonamides against 6-hydroxydopamine (6-OHDA)-induced neuronal SH-SY5Y cells. The effects of triazole derivatives on cell viability, intracellular reactive oxygen species (ROS) production, lactate dehydrogenase (LDH) leakage, and sirtuin 1 (SIRT1) activity were evaluated in the 6-OHDA-induced cells. The results indicated that six compounds (2a - 5a and 3b - 4b) exhibited promising neuroprotective potentials due to their abilities to decrease intracellular ROS production and LDH leakage, along with increasing SIRT1 activity. Molecular docking was also conducted to reveal possible binding modes and interactions against the SIRT1 target through the key interacting residues of ILE223, LEU215, and PRO212. In silico pharmacokinetic prediction indicated that these compounds are drug-like molecules, possibly further developed as oral neuroprotective drugs. A set of possible PD-related targets of these six compounds is also highlighted for further investigations. Cytotoxicity assays in normal lung MRC-5 fibroblasts showed relatively high IC₅₀ values, indicating low toxicity and favorable safety profiles. In summary, these six 1,2,3-triazole-based sulfonamides might potentially be neuroprotective agents for further PD therapeutic development.