Sulfonyl Hydrazone Derivatives Targeting Glutathione Reductase: A Potential Strategy for Redox Modulation in Cancer

Glutathione reductase (GR) plays a pivotal role in cellular metabolism by maintaining redox balance and sulfhydryl homeostasis through the regeneration of reduced glutathione (GSH). In tumor cells, GR is overexpressed, supporting enhanced antioxidant defenses and neutralizing the detrimental effects of reactive oxygen species. In this study, a series of sulfonyl hydrazone analogs bearing phenolic Mannich base moieties were synthesized and characterized as potential GR inhibitors. The compounds exhibited inhibitory activity with IC₅₀ values ranging from 198.1 to 3013 nM. In silico analyses revealed that 6a binds to the NADP⁺ binding site of the hGR enzyme and interacts with key residues involved in electron transfer, leading to reduced enzyme activity. Compound 6a, the most potent hGR enzyme inhibitor identified in this study, exhibited cytotoxic effects against MCF-7, A549, and HeLa cancer cell lines with EC₅₀ values of ~1.52, ~17.5, and ~8.82 mM, respectively. Notably, compound 6a demonstrated only weak cytotoxicity at the millimolar level, particularly against the MCF-7 cell line. Given its strong inhibitory activity toward the hGR enzyme, enhancing the membrane permeability of compound 6a may improve its cellular uptake and potency, thereby supporting its potential as a promising anticancer drug candidate.