Synthesis, Adenosine Receptor Binding and Molecular Modeling Studies of Novel Thieno[2,3-d]pyrimidine Derivatives

Abstract

A series of new molecules containing a thieno[2,3-d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2-position as well as an oxo-group, imidazole or 1,2,4-triazole ring at 4-position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) were evaluated. Compounds 17-19 with a free amino group at 2-position along with the presence of an imidazole/1,2,4-triazole ring at 4-position of the scaffold showed selective binding affinities for hA_2A AR whereas carbamoylation of the amino group at 2-position (in presence of an oxo-group at 4-position of the scaffold) increased the affinity and selectivity of certain compounds (7-10) for hA₃ AR. Molecular dynamics simulation study of one of the most active compound 8 (K_i hA₁ > 30 μM, hA_2A = 0.65 μM, and hA₃ = 0.124 μM) revealed the role of important amino acid residues for imparting good affinity towards hA₃ and hA_2A ARs. Molecular docking studies were carried out for other compounds by using the crystal structure of hA_2A AR and a homology model of hA₃ AR to rationalize their structure activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.

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A new series of thieno[2,3-d]pyrimidine derivatives have been synthesized and evaluated in vitro for their binding affinities towards adenosine receptors (ARs) and in silico to gain insight into their molecular binding interactions with the hA_2A and hA₃ ARs.

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