Design, Synthesis, and <i>In Silico/In Vitro</i> Evaluation of Novel Hydroxypyranone-Dithiocarbamate Hybrids as Potential Neuroprotective Agents

Neuroinflammation and oxidative stress are primary drivers of neurodegenerative diseases. Consequently, the development of multi-target-directed ligands has emerged as a promising therapeutic strategy. In this study, a novel series of hydroxypyranone-dithiocarbamate hybrids was designed, synthesized, and evaluated for its neuroprotective potential. Safety and intracellular ROS mitigation were assessed via MTT and DCFDA assays in LPS-induced SH-SY5Y neuroblastoma cells, while selective toxicity was profiled against MDA-MB-231 breast cancer and healthy HEK293-T cells. Comprehensive in silico profiling included ADMET predictions, molecular docking, and 100-ns molecular dynamics simulations targeting the anti-inflammatory cytokine IL-38. The in vitro results indicated that Compound 2, featuring a thiazolidine ring, emerged as the most promising lead derivative. It established a safe therapeutic window at 10 µM in neuronal cells while exhibiting specific cytotoxicity against cancer lines. Cytotoxicity evaluations on healthy HEK293-T cells revealed that the compounds possess a high safety profile, with IC50 values exceeding 100 µM. Compound 2 significantly reduced oxidative stress (mitigating LPS-induced ROS accumulation to 83.54% at a 10 µM dose), while in silico models, supported by highly stable thermodynamics (ΔG∼-19 kcal/mol), indicated that the IL-38 interface might serve as a plausible target for this novel scaffold. In conclusion, the integration of synthetic chemistry, in vitro biological evaluations, and computational thermodynamics reveals that hybridizing hydroxypyranone and dithiocarbamate pharmacophores offers a highly effective and safe scaffold for discovering novel neuroprotective agents targeting neuroinflammation.