Structure-based optimization of coumarin hA3 adenosine receptor antagonists

Journal article

Adenosine receptors are involved in several physiological processes. Molecules able to selectively modulate one of these receptors represent promising multifunctional agents to treat or slow down the progression of different diseases. 3-Arylcoumarins have already been studied as neuroprotective agents by our group. Here, differently 8-substituted 3-arylcoumarins are complementarily studied as ligands of adenosine receptors, performing radioligand binding assays. Among the synthesized compounds, selective A3 receptor antagonists have been identified. 3-(4-Bromophenyl)-8-hydroxycoumarin (compound 4) proved to be the most potent and selective A3 receptor antagonist (Ki = 258 nM). An analysis of its X-ray diffraction provided detailed information on its structure. Further evaluation of a selected series of compounds indicated that it is the nature and position of the substituents that determine their activity and selectivity. Theoretical modeling calculations corroborate and explain the experimental data, suggesting this novel scaffold has desirable properties for the development of potential multitarget drug candidates.

Authors: Matos, M; Vilar, S; Vazquez-Rodriguez, S; Kachler, S; Klotz, K

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Journal of Medicinal Chemistry
• Volume: 63
• Issue: 5
• Pages: 2577–2587
• Publication date: 2019-11-18
• DOI: 10.1021/acs.jmedchem.9b01572
• EISSN: 1520-4804
• ISSN: 0022-2623
• Language: English
• Keywords: FFR