Lead optimization and biological evaluation of diazenylbenzenesulfonamides inhibitors against glyoxalase-I enzyme as potential anticancer agents

Buthina A Al-Oudat; Nizar A Al-Shar'i; Qosay A Al-Balas; Suaad A Audat; Mohammad A Y Alqudah; Ali H Hamzah; Ramez W Hallak; Mel Bedi; Amanda Bryant-Friedrich

doi:10.1016/j.bioorg.2022.105657

Lead optimization and biological evaluation of diazenylbenzenesulfonamides inhibitors against glyoxalase-I enzyme as potential anticancer agents

Bioorg Chem. 2022 Mar:120:105657. doi: 10.1016/j.bioorg.2022.105657. Epub 2022 Feb 5.

Authors

Buthina A Al-Oudat¹, Nizar A Al-Shar'i², Qosay A Al-Balas², Suaad A Audat³, Mohammad A Y Alqudah⁴, Ali H Hamzah⁵, Ramez W Hallak⁵, Mel Bedi⁵, Amanda Bryant-Friedrich⁵

Affiliations

¹ Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan. Electronic address: baoudat@just.edu.jo.
² Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
³ Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
⁴ Department of Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
⁵ Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43606, USA.

PMID: 35152183
DOI: 10.1016/j.bioorg.2022.105657

Abstract

In a previous report, we described the discovery of (E)-5-((8-hydroxyquinolin-5-yl)diazenyl)-2-methylbenzenesulfonamide as a potent inhibitor of GLO-I enzyme with IC₅₀ of 1.28 ± 0.12 μM. Herein, lead optimization of this compound was achieved through targeting the central zinc atom and hydrophilic amino acid residues in the active site of the enzyme. Among the synthesized compounds, compound TS010 showed the most potent inhibitory activity with IC₅₀ of 0.57 ± 0.04 μM. Compound TS013 also showed comparable activity to that of the lead compound with IC₅₀ of 1.14 ± 0.03 μM. Molecular docking studies disclosed the binding mode of the compounds inside the active side of GLO-I enzyme.

Keywords: Anticancer; Glyoxalase-I; Lead Optimization; MM-PBSA; Molecular Docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Lactoylglutathione Lyase* / chemistry
Lactoylglutathione Lyase* / metabolism
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Enzyme Inhibitors
Lactoylglutathione Lyase