Synthesis and adenosine receptor binding studies of some novel triazolothienopyrimidines

A new series of 5-alkyl/aryl-8,9-dimethyl/8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thiones (4a–k) have been synthesized through a facile cyclization reaction of 4-hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (3a–k) using carbon disulphide under basic conditions. 4-Hydrazino-2-alkyl/aryl-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (3a–k) were prepared by replacing the chloro group of 4-chloro-2-substituted-5,6-dimethyl/5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidines (2a–k) with hydrazine hydrate which were obtained by a known one-pot synthesis. The affinities of these compounds for adenosine A1/A2A receptors were determined at 1 μM concentration. The test compounds which exhibited more than 20% inhibition were selected and further screened at six different concentration levels to estimate their EC50/Ki values. The most potent compounds in the series were 4c and 4d having an ethyl side chain at C5 position with dimethyl and cyclohexyl substitution at the C8–C9 positions, exhibiting Ki values of 2.1 and 1.1 μM, respectively, at A1ARs. The SAR indicates that by increasing or decreasing the alkyl chain length at C5 led to reduced affinity. The remaining aryl/arylalkyl derivatives of the series were inactive showing that a simple alkyl side chain at C5 is necessary for these ligands to bind at A1ARs. However, none of the compounds showed inhibition on A2A receptors at 1 μM concentration indicating their selectivity. This communication describes the design, synthesis and evaluation of these new molecules.

Graphical abstractA series of 5-alkyl/aryl-8,9-dimethyl/8,9,10,11-tetrahydro[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thiones have been synthesized. The affinities of these compounds for adenosine A1/A2a receptors were measured at 1 μM concentration. Some of the compounds have shown Ki values in the range of 1.0–4.0 μM.Figure optionsDownload full-size imageDownload as PowerPoint slide