TY - JOUR T1 - 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. AU - Załuski,Michał, AU - Schabikowski,Jakub, AU - Schlenk,Miriam, AU - Olejarz-Maciej,Agnieszka, AU - Kubas,Bartłomiej, AU - Karcz,Tadeusz, AU - Kuder,Kamil, AU - Latacz,Gniewomir, AU - Zygmunt,Małgorzata, AU - Synak,David, AU - Hinz,Sonja, AU - Müller,Christa E, AU - Kieć-Kononowicz,Katarzyna, Y1 - 2019/02/02/ PY - 2018/12/04/received PY - 2019/01/25/revised PY - 2019/02/01/accepted PY - 2019/2/28/pubmed PY - 2020/2/28/medline PY - 2019/2/28/entrez KW - Adenosine A(2A) receptors ligands KW - Annelated xanthines KW - Hepatotoxicity KW - Molecular docking KW - Monoamine oxidase B inhibitors KW - Neurodegenerative diseases KW - Parkinson’s disease SP - 1195 EP - 1210 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 27 IS - 7 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/30808606/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_ DB - PRIME DP - Unbound Medicine ER -