9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors

Marili V N Rodrigues; Alexandre F Barbosa; Júlia F da Silva; Deborah A dos Santos; Kenia L Vanzolini; Marcela C de Moraes; Arlene G Corrêa; Quezia B Cass

doi:10.1016/j.bmc.2015.12.006

9-Benzoyl 9-deazaguanines as potent xanthine oxidase inhibitors

Bioorg Med Chem. 2016 Jan 15;24(2):226-31. doi: 10.1016/j.bmc.2015.12.006. Epub 2015 Dec 8.

Authors

Marili V N Rodrigues¹, Alexandre F Barbosa², Júlia F da Silva², Deborah A dos Santos², Kenia L Vanzolini³, Marcela C de Moraes⁴, Arlene G Corrêa⁵, Quezia B Cass⁶

Affiliations

¹ Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Universidade Estadual de Campinas, 13148-218 Paulínia, SP, Brazil; Separare-Nucleo de Pesquisa em Cromatografia, Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil.
² Laboratório de Síntese de Produtos Naturais-LSPN, Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil.
³ Separare-Nucleo de Pesquisa em Cromatografia, Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil.
⁴ Separare-Nucleo de Pesquisa em Cromatografia, Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil; Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, 24020-141 Niterói, RJ, Brazil.
⁵ Laboratório de Síntese de Produtos Naturais-LSPN, Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil. Electronic address: agcorrea@ufscar.br.
⁶ Separare-Nucleo de Pesquisa em Cromatografia, Departamento de Química, Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil. Electronic address: quezia@pq.cnpq.br.

PMID: 26712096
DOI: 10.1016/j.bmc.2015.12.006

Abstract

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±9.80 nM, about thirty times more potent than allopurinol. Further details of synthesis and enzymatic studies are presented herein.

Keywords: 9-Deazaguanine; Allopurinol; Green synthesis; Microwave; Non-competitive inhibition; On-flow bidimensional liquid chromatography; Xanthine oxidase inhibitor.

Publication types

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

MeSH terms

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*
Guanine / analogs & derivatives*
Guanine / chemical synthesis
Guanine / chemistry
Guanine / pharmacology
Humans
Molecular Structure
Purine-Nucleoside Phosphorylase / antagonists & inhibitors
Purine-Nucleoside Phosphorylase / metabolism
Schistosoma mansoni / enzymology
Structure-Activity Relationship
Xanthine Oxidase / antagonists & inhibitors*
Xanthine Oxidase / metabolism

Substances

Benzyl Compounds
Enzyme Inhibitors
9-benzyl-9-deazaguanine
Guanine
Xanthine Oxidase
Purine-Nucleoside Phosphorylase