Multicomponent Assembly of Diverse Pyrazin-2(1<i>H</i>)‑one Chemotypes

An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2­(1<i>H</i>)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner

Multicomponent Assembly of Diverse Pyrazin-2(1<i>H</i>)‑one Chemotypes

An expedient and concise Ugi-based approach for the rapid assembly of pyrazin-2­(1<i>H</i>)-one-based frameworks has been developed. This convergent approach encompasses skeletal, functional and stereochemical diversity, exhibiting an unusually high bond-forming efficiency as well as high structure and step economies. The method involves the use of readily available commercial reagents and is an example of the reconciliation of structural complexity with operational simplicity in a time- and cost-effective manner

Copper-Catalyzed Huisgen 1,3-Dipolar Cycloaddition under Oxidative Conditions: Polymer-Assisted Assembly of 4‑Acyl-1-Substituted-1,2,3-Triazoles

We herein document the first example of a reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions. The combined use of two polymer-supported reagents (polystyrene-1,5,7-triaza­bicyclo­[4,4,0]­dec-5-ene/Cu and polystyrene-2-iodoxy­benzamide) overcomes the thermodynamic instability of copper­(I) species toward oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-dipolar cycloadditions in the presence of an oxidant agent. This polymer-assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu­(I)-catalyzed alkyne–azide cycloaddition

Three-Component Assembly of Structurally Diverse 2‑Aminopyrimidine-5-carbonitriles

An expedient route for the synthesis of libraries of diversely decorated 2-aminopyrimidine-5-carbonitriles is reported. This approach is based on a three-component reaction followed by spontaneous aromatization

Enantiospecific Recognition at the A_2B Adenosine Receptor by Alkyl 2‑Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates

A novel family of structurally simple, potent, and selective nonxanthine A_2BAR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (<b>16</b>) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (<b>16</b>) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(±)<b>16b</b>, <i>K</i>_i <b>=</b> 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A_2BAR, with the (<i>S</i>)-<b>16b</b> enantiomer retaining all the affinity (<i>K</i>_i <b>=</b> 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A_2B adenosine receptor and opens new possibilities in ligand design for this receptor

Discovery of Potent and Highly Selective A_2B Adenosine Receptor Antagonist Chemotypes

Three novel families of A_2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2­(1<i>H</i>)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A_2B ligand that exhibits complete selectivity toward A₁, A_2A, and A₃ receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A_2A receptor

Discovery of Potent and Highly Selective A_2B Adenosine Receptor Antagonist Chemotypes

Three novel families of A_2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2­(1<i>H</i>)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A_2B ligand that exhibits complete selectivity toward A₁, A_2A, and A₃ receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A_2A receptor

Effect of Nitrogen Atom Substitution in A₃ Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists

We report the first family of 2-acetamidopyridines as potent and selective A₃ adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (<i>K</i>_i < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA₃AR, and exemplifies the benefits of a joint theoretical–experimental approach to identify novel hA₃AR antagonists through succinct and efficient synthetic methodologies

Discovery of 3,4-Dihydropyrimidin-2(1<i>H</i>)‑ones As a Novel Class of Potent and Selective A_2B Adenosine Receptor Antagonists

We describe the discovery and optimization of 3,4-dihydropyrimidin-2­(1<i>H</i>)-ones as a novel family of (nonxanthine) A_2B receptor antagonists that exhibit an unusually high selectivity profile. The Biginelli-based hit optimization process enabled a thoughtful exploration of the structure–activity and structure–selectivity relationships for this chemotype, enabling the identification of ligands that combine structural simplicity with excellent hA_2B AdoR affinity and remarkable selectivity profiles

Effect of Nitrogen Atom Substitution in A₃ Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists

We report the first family of 2-acetamidopyridines as potent and selective A₃ adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (<i>K</i>_i < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA₃AR, and exemplifies the benefits of a joint theoretical–experimental approach to identify novel hA₃AR antagonists through succinct and efficient synthetic methodologies