16F16

**16F16** is a small molecule irreversible inhibitor of **protein disulfide isomerase (PDI)**, a chaperone enzyme in the endoplasmic reticulum involved in protein folding. It covalently modifies the two active site cysteines (C36 and C39) in the PDI *a* domain via its chloroacetyl group, suppressing PDI reductase activity and preventing apoptosis induced by misfolded proteins such as mutant huntingtin in PC12 cells and Aβ peptide in rat neurons. Originally identified in a high-throughput screen for neuroprotective compounds in Huntington's disease models, it demonstrates efficacy in cell and organotypic brain slice cultures but is distinguished from reversible PDI inhibitors like LOC14 and securinine by its irreversible binding mechanism.