کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10584382 981330 2013 60 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
1,3-Dialkyl-substituted tetrahydropyrimido[1,2-f]purine-2,4-diones as multiple target drugs for the potential treatment of neurodegenerative diseases
چکیده انگلیسی
Adenosine receptors and monoamine oxidases are drug targets for neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In the present study we prepared a library of 55 mostly novel tetrahydropyrimido[2,1-f]purinediones with various substituents in the 1- and 3-position (1,3-dimethyl, 1,3-diethyl, 1,3-dipropyl, 1-methyl-3-propargyl) and broad variation in the 9-position. A synthetic strategy to obtain 3-propargyl-substituted tetrahydropyrimido[2,1-f]purinedione derivatives was developed. The new compounds were evaluated for their interaction with all four adenosine receptor subtypes and for their ability to inhibit monoamine oxidases (MAO). Introduction of mono- or di-chloro-substituted phenyl, benzyl or phenethyl residues at N9 of the 1,3-dimethyl series led to the discovery of a novel class of potent MAO-B inhibitors, the most potent compound being 9-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione (21g, IC50 human MAO-B: 0.0629 μM), which displayed high selectivity versus the other investigated targets. Potent dually active A1/A2A adenosine receptor antagonists were identified, for example, 9-benzyl-1-methyl-3-propargyl-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)dione (19f, Ki, human receptors, A1: 0.249 μM, A2A: 0.253 μM). Several compounds showed triple-target inhibition, the best compound being 9-(2-methoxybenzyl)-1-methyl-3-(prop-2-ynyl)-6,7,8,9-tetrahydro pyrimido [1,2-f]purine-2,4(1H,3H)-dione (19g, Ki A1: 0.605 μM, Ki A2A: 0.417 μM, IC50 MAO-B: 1.80 μM). Compounds inhibiting several different targets involved in neurodegeneration may exhibit additive or even synergistic effects in vivo.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 23, 1 December 2013, Pages 7435-7452
نویسندگان
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