9 research outputs found
Integrated Ugi-Based Assembly of Functionally, Skeletally, and Stereochemically Diverse 1,4-Benzodiazepin-2-ones
A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.This work was financially supported by the Galician Government (Spain), Projects: 09CSA016234PR and GPC-2014-PG037. J.A. thanks FUNDAYACUCHO (Venezuela) for a predoctoral grant and DeputacioÌn da CorunÌa (Spain) for a postdoctoral research grant. A.N.-V. thanks the Spanish government for a RamoÌn y Cajal research contract
Multicomponent Assembly of Diverse Pyrazin-2(1<i>H</i>)âone Chemotypes
An expedient and
concise Ugi-based approach for the rapid assembly
of pyrazin-2Â(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>)âone Chemotypes
An expedient and
concise Ugi-based approach for the rapid assembly
of pyrazin-2Â(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 4âAcyl-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-triazaÂbicycloÂ[4,4,0]Âdec-5-ene/Cu
and polystyrene-2-iodoxyÂbenzamide) overcomes the thermodynamic
instability of copperÂ(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 CuÂ(I)-catalyzed
alkyneâazide
cycloaddition
Three-Component Assembly of Structurally Diverse 2âAminopyrimidine-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
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-2Â(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
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-2Â(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
Discovery of 3,4-Dihydropyrimidin-2(1<i>H</i>)âones As a Novel Class of Potent and Selective A<sub>2B</sub> Adenosine Receptor Antagonists
We
describe the discovery and optimization of 3,4-dihydropyrimidin-2Â(1<i>H</i>)-ones as a novel family of (nonxanthine) A<sub>2B</sub> receptor antagonists that exhibit an unusually high selectivity
profile. The Biginelli-based hit optimization process enabled a thoughtful
exploration of the structureâactivity and structureâselectivity
relationships for this chemotype, enabling the identification of ligands
that combine structural simplicity with excellent hA<sub>2B</sub> AdoR
affinity and remarkable selectivity profiles