Design, Synthesis and Biological Evaluation of 1,4-Benzenesulfonamide Derivatives as Glyoxalase I Inhibitors

Glyoxalase system is one of the defense cellular mechanisms that protect cells against endogenous harmful metabolites, mainly methylglyoxal (MG), through conversion of cytotoxic methylglyoxal into the non-toxic lactic acid. Glyoxalase system comprises of two enzymes glyoxalase I, glyoxalase II, and a catalytic amount of reduced glutathione. Cancerous cells overexpress glyoxalase I, making it a target for cancer therapy. Many studies have been conducted to identify potent Glx-I inhibitors.

Aiming to discover and develop novel Glx-I inhibitors, a series of 1,4-benzenesulfonamide derivatives were designed, synthesized, and biologically evaluated in vitro against human Glx-I enzyme. Seventeen compounds were designed based on the hit compound that was obtained from searching the National Cancer Institute (NCI) database. The synthesis of the target compounds (13-29) was accomplished utilizing an azo coupling reaction of aniline derivatives and activated substituted aromatic compounds. To understand the binding mode of the active compounds at the active site of Glx-I, docking studies were performed.

Structure activity relationship (SAR) studies were accomplished which led to the identification of several compounds that showed potent inhibitory activity with IC₅₀ values below 10 μM. Among the compounds tested, compounds (E)-2-hydroxy-5-((4-sulfamoylphenyl)diazenyl)benzoic acid (26) and (E)-4-((8-hydroxyquinolin-5-yl)diazenyl) benzenesulfonamide (28) displayed potent Glx-I inhibitory activity with IC₅₀ values of 0.39 μM and 1.36 µM, respectively. Docking studies of compounds 26 and 28 were carried out to illustrate the binding mode of the molecules into the Glx-I active site.

Our results show that compounds 26 and 28 displayed potent Glx-I inhibitory activity and can bind the Glx-I well. These findings should lead us to discover new classes of compounds with better Glx-I inhibition.