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

Author:

Spinaci Andrea1ORCID,Buccioni Michela1ORCID,Catarzi Daniela2ORCID,Cui Chang1,Colotta Vittoria2ORCID,Dal Ben Diego1ORCID,Cescon Eleonora3,Francucci Beatrice1,Grieco Ilenia3,Lambertucci Catia1ORCID,Marucci Gabriella1,Bassani Davide4ORCID,Pavan Matteo4ORCID,Varano Flavia2,Federico Stephanie3ORCID,Spalluto Giampiero3,Moro Stefano4ORCID,Volpini Rosaria1ORCID

Affiliation:

1. Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy

2. Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Dipartimento di Neuroscienze, Psicologia, Università degli Studi di Firenze, Via Ugo Schiff, 6, Sesto Fiorentino, 50019 Florence, Italy

3. Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy

4. Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy

Abstract

Based on a screening of a chemical library of A2A 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 (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called “dual anta-inhibitors”, demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the A2AAR. The N6-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (17, IC50 = 0.59 μM and KiA2A = 0.076 μM) showed the best balance of A2AAR affinity and CK1δ 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.

Funder

Italian Ministry of University and Research, PRIN 2017

Publisher

MDPI AG

Subject

Drug Discovery,Pharmaceutical Science,Molecular Medicine

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