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

Abstract 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, (IC50 = 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 IC₅₀ of 150 nM. These findings pave the way for the continued development of highly effective GLO-I inhibitors.