9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors

• Published in: Bioorganic & medicinal chemistry 2016-01, Vol.24 (2), p.226-231
• Main Authors: Rodrigues, Marili V.N., Barbosa, Alexandre F., da Silva, Júlia F., dos Santos, Deborah A., Vanzolini, Kenia L., de Moraes, Marcela C., Corrêa, Arlene G., Cass, Quezia B.
• Format: Article
• Language: English
• Subjects: 9-Deazaguanine; Allopurinol; Animals; Benzyl Compounds - chemical synthesis; Benzyl Compounds - chemistry; Benzyl Compounds - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Green synthesis; Guanine - analogs & derivatives; Guanine - chemical synthesis; Guanine - chemistry; Guanine - pharmacology; Humans; Microwave; Molecular Structure; Non-competitive inhibition; On-flow bidimensional liquid chromatography; Purine-Nucleoside Phosphorylase - antagonists & inhibitors; Purine-Nucleoside Phosphorylase - metabolism; Schistosoma mansoni - enzymology; Structure-Activity Relationship; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism; Xanthine oxidase inhibitor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.12.006

[Display omitted] A novel potent xanthine oxidase inhibitor, 3-nitrobenzoyl 9-deazaguanine (LSPN451), was selected from a series of 10 synthetic derivatives. The enzymatic assays were carried out using an on-flow bidimensional liquid chromatography (2D LC) system, which allowed the screening¸ the measurement of the kinetic inhibition constant and the characterization of the inhibition mode. This compound showed a non-competitive inhibition mechanism with more affinity for the enzyme–substrate complex than for the free enzyme, and inhibition constant of 55.1±9.80nM, about thirty times more potent than allopurinol. Further details of synthesis and enzymatic studies are presented herein.