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Novel multi-target directed ligands based on annelated xanthine scaffold with aromatic substituents acting on adenosine receptor and monoamine oxidase B. Synthesis, in vitro and in silico studies.
Zaluski, Michal; Schabikowski, Jakub; Schlenk, Miriam; Olejarz-Maciej, Agnieszka; Kubas, Bartlomiej; Karcz, Tadeusz; Kuder, Kamil; Latacz, Gniewomir; Zygmunt, Malgorzata; Synak, David; Hinz, Sonja; Müller, Christa E; Kiec-Kononowicz, Katarzyna.
Afiliação
  • Zaluski M; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Schabikowski J; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Schlenk M; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • Olejarz-Maciej A; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Kubas B; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Karcz T; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Kuder K; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Latacz G; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Zygmunt M; Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Synak D; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
  • Hinz S; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • Müller CE; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
  • Kiec-Kononowicz K; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland. Electronic address: mfkonono@cyf-kr.edu.pl.
Bioorg Med Chem ; 27(7): 1195-1210, 2019 04 01.
Article em En | MEDLINE | ID: mdl-30808606
N9-Benzyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones were designed as dual-target-directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blockade of monoamine oxidase B (MAO-B). A library of 37 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. A systematic modification of the tricyclic structures based on a xanthine core by enlargement of the third heterocyclic ring or attachment of various substituted benzyl moieties resulted in the development of 9-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (9u; Ki human A2AAR: 189 nM and IC50 human MAO-B: 570 nM) as the most potent dual acting ligand of the series displaying high selectivity versus related targets. Moreover, some potent, selective MAO-B inhibitors were identified in the group of pyrimido- and 1,3-diazepino[2,1-f]purinediones. Compound 10d (10-(3,4-dichlorobenzyl)-1,3-dimethyl-7,8,9,10-tetrahydro-1H-[1,3]diazepino[2,1-f]purine-2,4(3H,6H)-dione) displayed an IC50 value at human MAO-B of 83 nM. Analysis of structure-activity relationships was complemented by molecular docking studies based on previously published X-ray structures of the protein targets. An extended biological profile was determined for selected compounds including in vitro evaluation of potential hepatotoxicity calculated in silico and antioxidant properties as an additional desirable activity. The new molecules acting as dual target drugs may provide symptomatic relief as well as disease-modifying effects for neurodegenerative diseases, in particular Parkinson's disease.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Xantina / Receptor A2A de Adenosina / Antagonistas do Receptor A2 de Adenosina / Monoaminoxidase / Inibidores da Monoaminoxidase Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Polônia

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Xantina / Receptor A2A de Adenosina / Antagonistas do Receptor A2 de Adenosina / Monoaminoxidase / Inibidores da Monoaminoxidase Limite: Humans Idioma: En Revista: Bioorg Med Chem Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Polônia