5 research outputs found
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<sub>2B</sub> 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<sub>2B</sub>AR 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><sub>i</sub> <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<sub>2B</sub>AR, with the (<i>S</i>)-<b>16b</b> enantiomer retaining all the affinity
(<i>K</i><sub>i</sub> <b>=</b> 15.1 nM), as predicted
earlier by molecular modeling. This constitutes the first example
of enantiospecific recognition at the A<sub>2B</sub> adenosine receptor
and opens new possibilities in ligand design for this receptor
Discovery of Potent and Highly Selective A<sub>2B</sub> Adenosine Receptor Antagonist Chemotypes
Three novel families of A<sub>2B</sub> 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<sub>2B</sub> ligand that exhibits complete selectivity toward
A<sub>1</sub>, A<sub>2A</sub>, and A<sub>3</sub> 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<sub>2A</sub> receptor
Three-Dimensional Printing in Catalysis: Combining 3D Heterogeneous Copper and Palladium Catalysts for Multicatalytic Multicomponent Reactions
Two 3D-hybrid monolithic
catalysts containing immobilized copper
and palladium species on a silica support were synthesized by 3D printing
and a subsequent surface functionalization protocol. The resulting
3D monoliths provided a structure with pore sizes around 300 μm,
high mechanical strength, and easy catalyst recyclability. The devices
were designed to perform heterogeneous multicatalytic multicomponent
reactions (MMCRs) based on a copper alkyne–azide cycloaddition
(CuAAC) + palladium catalyzed cross-coupling (PCCC) strategy, which
allowed the rapid assembly of variously substituted 1,2,3-triazoles
using a mixture of tBuOH/H<sub>2</sub>O as solvent. The reusable multicatalytic
system developed in this work is an example of a practical miniaturized
and compartmental heterogeneous 3D-printed metal catalyst to perform
MMCRs for solution chemistry
Discovery of Potent and Highly Selective A<sub>2B</sub> Adenosine Receptor Antagonist Chemotypes
Three novel families of A<sub>2B</sub> 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<sub>2B</sub> ligand that exhibits complete selectivity toward
A<sub>1</sub>, A<sub>2A</sub>, and A<sub>3</sub> 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<sub>2A</sub> receptor