10381-75-6Relevant articles and documents
The synthesis, characterization and biological evaluation of a new nitric oxide donor agent
Profire, Lenuta,Apotrosoaei, Maria,Oprea, Anca,Brebu, Mihai,Lupascu, Florentina,Lupusoru, Catalina Elena,Vasile, Cornelia
, p. 389 - 400 (2014)
The synthesis of a new xanthine nitric oxide donor (TSP-81) is discussed. The designed compound included two structural moieties, i.e., theophylline (1,3-dimethylxanthine) and acetaminophen (4-hydroxyacetanilide), linked by the nitric oxide donor alkyl chain as a spacer. The compound was characterized by microanalysis (CHN), 1H-NMR, 13C-NMR, FT-IR and UV-Vis spectroscopy and thermogravimetric analysis. The thermal behaviour showed that TSP-81 melts with decomposition in four steps, the most important ones being the 2nd one (the registered weight loss being 17.6 %) and the 3 rd one (with a registered weight loss of 30.4 %). The toxicity degree, the anti-inflammatory effect and the ability of releasing nitric oxide of TSP-81 was also evaluated. The biological assays established that TSP-81 exhibits enhanced biological properties, such as lower toxicity and higher anti-inflammatory effect, compared to theophylline and acetaminophen, the drugs used as the parent molecules. Thus, TSP-81 is approximately 2 times more active than theophylline and 4 times more active than acetaminophen in reducing cotton pellet granuloma formation. Furthermore, the release of nitric oxide (NO) appears to play an important role in enhancing the anti-inflammatory effect.
Thietanyl protection in the synthesis of 1-alkyl-8-bromo-3-methyl-3,7- dihydro-1H-purine-2,6-diones
Khaliullin,Shabalina,Sharafutdinov
, p. 689 - 692 (2010)
The protection of the 7-NH group in 8-bromo-3-methyl-3,7-dihydro-1H-pyrine- 2,6-dione during the synthesis of 7-ubsubstituted 1-alkyl-8-bromo-3-methyl-3,7- dihydro-1H-pyrine-2,6-diones with a thienyl group was applied that was introduced by the reaction with 2-chloromethylthiirane. The thietanyl protection was removed by treating with sodium alcoholate after the oxidation with hydrogen peroxide to thietane 1,1-dioxide group. Pleiades Publishing, Ltd., 2010.
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
Za?uski, Micha?,Schabikowski, Jakub,Schlenk, Miriam,Olejarz-Maciej, Agnieszka,Kubas, Bart?omiej,Karcz, Tadeusz,Kuder, Kamil,Latacz, Gniewomir,Zygmunt, Ma?gorzata,Synak, David,Hinz, Sonja,Müller, Christa E.,Kie?-Kononowicz, Katarzyna
, p. 1195 - 1210 (2019/02/26)
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.
Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones
Drabczyńska, Anna,Yuzlenko, Olga,K?se, Meryem,Paskaleva, Minka,Schiedel, Anke C.,Karolak-Wojciechowska, Janina,Handzlik, Jadwiga,Karcz, Tadeusz,Kuder, Kamil,Müller, Christa E.,Kie?-Kononowicz, Katarzyna
scheme or table, p. 3590 - 3607 (2011/11/05)
Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3- dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A1 and A2A receptors. Selected compounds were additionally investigated for affinity to the human A1, A2A, A2B and A 3 receptor subtypes. The results of the radioligand binding assays at adenosine A1 and A2A receptors showed that most of the compounds exhibited adenosine A2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A2A affinity. The most potent A2A ligands of the present series were compounds 6 (Ki 0.33 μM rat A2A, 0.31 μM human A2A), 8 (Ki 0.98 μM rat A2A, 0.42 μM human A2A) and 15 (Ki 0.24 μM rat A2A, 0.61 μM human A2A) with the latter one showing high A 2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A2A receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q2 = 0.88) for A2A AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A2A antagonists with good water-solubility.
