Coumarins and adenosine receptors: New perceptions in structure–affinity relationships

Abstract

Adenosine receptor (AR) subtypes are involved in several physiological and pharmacological processes. Ligands that are able to selectively modulate one receptor subtype can delay or slow down the progression of diverse diseases. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on coumarin scaffold. Therefore, a series of 3‐phenylcarboxamidocoumarins were synthesized and their affinity for the human AR subtypes was screened by radioligand binding assays for A1, A2A and A3 receptors and for A2B by adenylyl cyclase assay. Compound 26 was found to be the most remarkable, with a hA1/hA3 and hA2A/hA3 selectivity of 42, for the A3 AR (Ki = 2.4 μm). Receptor‐driven molecular modelling studies have provided valuable information on the binding/selectivity data of compound 26 and for the following optimization process. Moreover, compound 26 presents drug‐like properties according to the general guidelines linked to the concept.

Adenosine Receptor Ligands: Coumarin–Chalcone Hybrids as Modulating Agents on the Activity of hARs

“…Having in mind that both the coumarin and chalcone nuclei are structurally close to flavonoids, the design of novel AR ligands based on their scaffolds emerged as an interesting idea. Our study was also motivated by the structural similarity between the coumarin and the chromone scaffolds, which were previously described as AR ligands [ 35 , 36 ], and by the similarities with some coumarin derivatives previously described in our group [ 37 , 38 , 39 , 40 , 41 , 42 ]. In this context, we focused our attention on the 3-benzoylcoumarin core, considered as a hybrid scaffold in which the chalcone is fixed in a trans conformation through the double bond of the pyrone ring of the coumarin skeleton ( Figure 1 ), presenting a more restricted conformation compared to the previously described coumarin–chalcone hybrids [ 36 ].…”

A Primary Amide-Functionalized Heterogeneous Catalyst for the Synthesis of Coumarin-3-carboxylic Acids via a Tandem Reaction

“…Here, we have established its synthesis in two steps, where coumarin-3carboxylic acid is a key intermediate. By following the previously reported procedure, 72 coumarin-3-phenylcarboxamide was synthesized from coumarin-3-carboxylic acid as a yellow solid in an overall 71% yield (for detailed synthetic procedure and 1 H NMR spectrum, see Figure S15). Mechanistic Study.…”

Structure-Based Optimization of Coumarin hA3 Adenosine Receptor Antagonists

“…14 These particular effects aroused our attention, since our group has been active in the research of age-related pathologies, in particular vascular, inflammatory and neurodegenerative diseases. 15 Based on the background of our research group regarding differently substituted coumarins as potential adenosine receptor ligands, 16,17,18,19,20,21 and in the potential of some of these compounds as neuroprotectors and enzymatic inhibitors related to neurodegenerative disorders (i.e. acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B), in this work we report a group of coumarins bearing a wide variety of substituents as modulators of adenosine receptors.…”

“…On the basis of the background of our research group regarding differently substituted coumarins as potential adenosine receptor ligands − and in the potential of some of these compounds as neuroprotectors and enzymatic inhibitors related to neurodegenerative disorders (i.e., acetylcholinesterase, butyrylcholinesterase, and monoamine oxidase B), in this work, we report a group of coumarins bearing a wide variety of substituents as modulators of adenosine receptors. In particular, the revealing achievements of our last work on the interesting activity of 8-substituted 3-arylcoumarins (Figure ) have been the inspiration for the progression of this study .…”