RESUMO
Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-gamma-carboline 5b (2,8-dimethyl-5-[cis-2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H(1) and serotonin 5-HT(6) receptors (IC(50) < 0.45 microM and IC(50) = 0.73 microM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity.
Assuntos
Carbolinas/síntese química , Carbolinas/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/farmacologia , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
Synthesis, biological evaluation and structure-activity relationships for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, gamma-carbolines 3{8} and 3{14} have been identified as potent small molecule antagonists of histamine H(1) (IC(50)=0.1 microM) and serotonin 5-HT(6) (IC(50)=0.37 microM) receptors, respectively.
Assuntos
Carbolinas/química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/química , Carbolinas/síntese química , Carbolinas/farmacologia , Linhagem Celular , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Indóis/química , Concentração Inibidora 50 , Receptores Histamínicos H1/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
In this work, we explored several original combinatorial derivatization patterns for the 3,4-dihydro-2H-1,4-benzothiazine scaffold. The synthesis begins with commercially available 4-chloro- and 4-fluoro-3-nitrobenzoates and employs a sequence of moderate and high-yielding reactions that display a relatively high substituent tolerance. Simple manual techniques for parallel reactions were coupled with easy workup and purification procedures to give high-purity final products. The developed approach was easily adaptable for parallel synthesis of more than 2600 novel 2H-benzo[1,4]thiazine-6-carboxylic acid amides, which were efficiently prepared in a semiautomatic fashion using special CombiSyn synthesizers.
Assuntos
Cromatografia Líquida/métodos , Técnicas de Química Combinatória , Tiazinas/síntese química , Desenho de Fármacos , Estrutura MolecularRESUMO
Two efficient strategies for solution-phase parallel synthesis of libraries of quinoline derivatives are described. The first synthetic pathway features the Pfitzinger reaction of isatin with diethyl malonate and sulfochlorination of the resulting 2-oxo-1,2-dihydroquinoline-4-carboxylate followed by generation of sulfonamide library. The second strategy employs the unusual behavior of 5-sulfamoylisatins in Pfitzinger reactions, which results in formation of 6-sulfamoyl-4-carboxyquinolines instead of the anticipated 2-oxo-1,2-dihydroquinoline structures. The obtained carboxylates appeared to be convenient synthetic intermediates for the generation of the corresponding carboxamide libraries. Using these reagents, the parallel solution-phase synthesis of more than 500 substituted quinoline and 2-oxo-1,2-dihydroquinoline derivatives has been accomplished on the 50-100-mg scale. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures to give high-purity final products. The scope and limitations of the developed approaches are discussed.
Assuntos
Técnicas de Química Combinatória/métodos , Desenho de Fármacos , Quinolinas/síntese química , Sulfonamidas/síntese química , Estrutura Molecular , Quinolinas/química , Sulfonamidas/químicaRESUMO
The parallel solution-phase synthesis of a series of building blocks and combinatorial libraries based on natural bispidine scaffold has been accomplished. Key reactions include catalytic hydrogenation of the (-)-cytisine heterocyclic system, followed by alkali-mediated ring cleavage. Using this approach, a series of new bispidine core building blocks for combinatorial synthesis with three points of diversity were effectively synthesized. The libraries from libraries were then obtained in good yields and purities using solution-phase acylation reactions. Obtained combinatorial libraries of 3,4,7-trisubstituted bispidines are potentially useful in the discovery of novel physiologically active compounds.