Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists.

first_page settings Order Article Reprints Open AccessArticle Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists by Amélie Laversin , Robin Dufossez †, Raphaël Bolteau † [ORCID] , Romain Duroux , Séverine Ravez , Sergio Hernandez-Tapia , Martin Fossart , Mathilde Coevoet [ORCID] , Maxime Liberelle , Saïd Yous , Nicolas Lebègue [ORCID] and Patricia Melnyk * [ORCID] Univ. Lille, Inserm, CHU Lille, U1172—LilNCog—Lille Neuroscience & Cognition, F-59000 Lille, France * Author to whom correspondence should be addressed. † These authors contributed equally to this work. Molecules 2024, 29(16), 3847; https://doi.org/10.3390/molecules29163847 Submission received: 11 July 2024 / Revised: 31 July 2024 / Accepted: 5 August 2024 / Published: 14 August 2024 (This article belongs to the Special Issue Heterocycles in Medicinal Chemistry III) Download keyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract The adenosine A2A receptor (A2AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 (Ki (hA2AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound 5m showed a high affinity for hA2AR with a Ki value of 5 nM and demonstrated antagonist activity with an IC50 of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (9x, Ki = 21 nM; 10d, Ki = 15 nM) and functional antagonist activities (9x, IC50 = 9 µM; 10d, IC50 = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A2AR antagonists for therapeutic applications.