Dual Anta-Inhibitors of the A2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies

Based on a screening of a chemical library of A(2A) adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1 delta) and to bind adenosine receptors (ARs). Some derivatives, here called dual anta-inhibitors , demonstrated good CK1 delta inhibitory activity combined with a high binding affinity, especially for the A(2A)AR. The N-6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 mu M and KiA(2A) = 0.076 mu M) showed the best balance of A(2A)AR affinity and CK1 delta inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein-ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor 17 could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases.

Automated summary

Through screening of a chemical library, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of CK1 delta and to bind ARs. The compound N-6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17) showed the best balance of A(2A)AR affinity and CK1 delta inhibitory activity. Computational studies were performed to simulate the protein-ligand interactions. Therefore, compound 17 could be considered a lead compound for the treatment of chronic neurodegenerative and cancer diseases with synergistic effects.