Design, Synthesis and Biological Evaluation of Potential Novel Zinc Binders Targeting Human Glyoxalase-I; A Validated Target for Cancer Treatment

Abstract

The concept of using glyoxalase-I (Glo-I) enzyme inhibitors as anticancer agents is now becoming well-recognized due to the important role the enzyme plays in the detoxification of cytotoxic aldehydes such as methylglyoxal (MG) to harmless substances. In this study, a series of potential Glo-I inhibitor candidates possessing a zinc binding group were synthesized based on structure-based design using Discovery Studio (DS) 3.5 from Biovia. LibDock protocol was used to dock the compounds onto the active site of Glo-I. N-substituted aminobenzamide scaffolds were chosen, and 14 compounds were synthesized, fully characterized and tested in vitro against the target enzyme. A strong positive correlation was noticed between in silico and experimental data. The top ranked compound (compound 14), which was also the most active experimentally, showed 75.9% inhibition at a 50 μM concentration.