Structural optimization and biological evaluation of quinoline/naphthalene-based glyoxalase-I inhibitors as anti-cancer candidates

The glyoxalase system, inherent in mammalian cells, serves as a natural detoxification mechanism that regulates cytotoxic byproducts, especially methylglyoxal (MG). Consisting of glyoxalase I (Glo-I), glyoxalase II (Glo-II), and glutathione (GSH), this system plays a vital role in managing these harmful substances. Glo-I catalyzes the rate-limiting step in MG detoxification and is found to be overexpressed in different cancer types, rendering it a promising target for novel anticancer drugs. In a previous study, a series of diazenylbenzenesulfonamide derivatives were synthesized and evaluated for their activity against Glo-I. Among these compounds, HA1, A1, and HA2 were identified as Glo-I inhibitors with IC₅₀ values of 1.36 ± 0.09, 1.36 ± 0.01, and 1.22 ± 0.07 µM, respectively, and were subsequently chosen as lead compounds for further investigation. In the present study, the lead compounds were subjected to structural optimization to develop more potent inhibitors. Various derivatives with distinct chemical features were synthesized and tested in vitro against Glo-I to establish their structure-activity relationship and determine the key interactions within the enzyme’s active site. Several compounds exhibited potent inhibitory activity with sub-micromolar IC₅₀ values. Notably, compound (E)-8-hydroxy-5-((4-(N-(thiazol-2-yl)sulfamoyl)phenyl)diazenyl)quinoline-2-carboxylic acid (B9) emerged as the most potent compound, with IC₅₀ value of 0.44 ± 0.06 µM. The structure-activity relationship analysis of compound B9 underscored the significance of the 8-hydroxyquinoline moiety as well as the sulfathiazole moiety for its inhibitory activity. To gain deeper insights into the binding modes of the compounds within the enzyme’s active site, molecular docking studies were conducted, providing enhanced and accurate predictions.