Design, Synthesis and Biological Evaluation of Potent Thiazolidinedione Salicylic Acid Inhibitors Against Glyoxalase-I as Potential Anticancer Agents

The worldwide rise in cancer incidence and mortality rates has spurred the search for new pathways implicated in cancer development and progression. One such target is glyoxalase 1 (GLO-I), a key player in methylglyoxal detoxification and a factor in the proliferation and prognosis of numerous cancers. Recent studies led by Al-Shar’i et al utilized computer-aided drug design to identify potential inhibitors of GLO-I. The second most potent hit, ( Z )-5-(5-((2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)-2-hydroxybenzoic acid, (IC ₅₀  = 4.24 µM), was selected as a lead for further optimization. Through molecular docking, 27 analogues were designed and evaluated for binding affinity, with 14 of the top-scorings synthesized and tested for their inhibitory activity against GLO-I. The majority of these analogues showed enhanced activities relative to the lead compound, with the most potent having an IC ₅₀ of 150 nM. These findings pave the way for the continued development of highly effective GLO-I inhibitors.