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Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3‐ d ]pyrimidine derivatives
Author(s) -
Deb Pran Kishore,
Mailavaram Raghuprasad,
Chandrasekaran Balakumar,
Kaki Venkata Rao,
Kaur Rajwinder,
Kachler Sonja,
Klotz KarlNorbert,
Akkinepally Raghuram Rao
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13155
Subject(s) - chemistry , stereochemistry , docking (animal) , pyrimidine , imidazole , selectivity , homology modeling , molecular model , triazole , ligand (biochemistry) , amino acid , receptor , enzyme , biochemistry , organic chemistry , catalysis , medicine , nursing
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 ( AR s) was 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 the presence of an oxo‐group at 4‐position of the scaffold) increased the affinity and selectivity of certain compounds ( 7–10 ) for hA 3 AR . Molecular dynamic simulation study of one of the most active compound 8 ( K i hA 1 > 30 μ m , hA 2A = 0.65 μ m , and hA 3 = 0.124 μ m ) revealed the role of important amino acid residues for imparting good affinity towards hA 3 and hA 2A AR s. Molecular docking studies were carried out for other compounds using the crystal structure of hA 2A AR and a homology model of hA 3 AR to rationalize their structure–activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.