Drug Design, Development and Therapy (Mar 2022)
Design, Synthesis and Biological Evaluation of 1,4-Benzenesulfonamide Derivatives as Glyoxalase I Inhibitors
Abstract
Suaad Abdallah Audat,1 Qosay Ali Al-Balas,2 Buthina Abdallah Al-Oudat,2 Mo’ad Jamil Athamneh,1 Amanda Bryant-Friedrich3 1Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, Irbid, 22110, Jordan; 2Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan; 3Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, 48202, USACorrespondence: Suaad Abdallah Audat, Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan, Tel +962 2 720 1000, Fax +962 2 720 1071, Email [email protected]: 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.Methods: 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.Results: 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.Conclusion: 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.Graphical Abstract: Keywords: anticancer agents, glyoxalase I, structure activity relationship, SAR, molecular docking
