RESUMO
Using a high-throughput, cell-based HCV luciferase reporter assay to screen a diverse small-molecule compound collection (â¼ 300,000 compounds), we identified a benzofuran compound class of HCV inhibitors. The optimization of the benzofuran scaffold led to the identification of several exemplars with potent inhibition (EC50 < 100 nM) of HCV, low cytotoxicity (CC50 > 25 µM), and excellent selectivity (selective index = CC50/EC50, > 371-fold). The structure-activity studies culminated in the design and synthesis of a 45-compound library to comprehensively explore the anti-HCV activity. The identification, design, synthesis, and biological characterization for this benzofuran series is discussed.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Benzofuranos/síntese química , Benzofuranos/farmacologia , Hepacivirus/efeitos dos fármacos , Antivirais/toxicidade , Benzofuranos/toxicidade , Linhagem Celular , Descoberta de Drogas , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Ensaios de Triagem em Larga Escala , Humanos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A number of functionally substituted 9-fluorenylidenes and 9,10-phenanthrenes have been synthesized from substituted o-halostyrenes and o-halo allylic benzenes respectively in good yields by the palladium-catalyzed annulation of arynes. The methodology tolerates a variety of functional groups, including cyano, ester, aldehyde, and ketone groups, occurs under relatively mild reaction conditions, and involves the generation of two new carbon-carbon bonds, thus providing these important carbocyclic ring systems in a single synthetic step.
Assuntos
Fluorenos/síntese química , Fenantrenos/síntese química , Compostos Alílicos , Benzeno , Catálise , Métodos , Paládio , EstirenosRESUMO
3-Iodoindoles have been synthesized by the iodocyclization of N,N-dialkyl-o-(1-alkynyl)anilines, obtained by the Pd/Cu catalyzed coupling of terminal acetylenes with N,N-dialkyl-o-iodoanilines. These 3-iodoindoles undergo palladium-catalyzed Sonogashira and Suzuki coupling reactions to yield 1,2,3-trisubstituted indoles. These reactions have been applied to parallel library synthesis utilizing commercially available terminal acetylenes and boronic acids. The aforementioned chemistry has also been carried out on a chlorinated Wang resin as a solid support, affording 1,2,3,5-tetrasubstituted indoles after cleavage from the support. A diverse 42-member library of highly substituted indoles has been synthesized.
Assuntos
Técnicas de Química Combinatória , Indóis/síntese química , Paládio/química , Catálise , Cromatografia Líquida de Alta Pressão , Indóis/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Dados de Sequência Molecular , SoluçõesRESUMO
The palladium-catalyzed annulation of arynes by substituted o-halostyrenes produces substituted 9-fluorenylidenes in good yields. This methodology provides this important carbocyclic ring system in a single step, which involves the generation of two new carbon-carbon bonds, occurs under relatively mild reaction conditions, and tolerates a variety of functional groups, including cyano, ester, aldehyde, and ketone groups.
Assuntos
Fluorenos/síntese química , Paládio/química , Catálise , Técnicas de Química Combinatória , Ciclização , Fluorenos/química , Estrutura Molecular , Estirenos/químicaRESUMO
The palladium-catalyzed aminocarbonylation of o-halobenzoates produces 2-substituted isoindole-1,3-diones in good yields. This methodology provides a good one-step approach to this important class of heterocycles and tolerates a variety of functional groups, including methoxy, alcohol, ketone, and nitro groups.
Assuntos
Aminas/química , Bromobenzoatos/química , Clorobenzoatos/química , Iodobenzoatos/química , Isoindóis/síntese química , Paládio/química , Catálise , Ciclização , Isoindóis/química , Estrutura Molecular , EstereoisomerismoRESUMO
The electrophilic cyclization of substituted propargylic aryl ethers by I2, ICl, and PhSeBr produces 3,4-disubstituted 2H-benzopyrans in excellent yields. This methodology results in vinylic halides or selenides under mild reaction conditions and tolerates a variety of functional groups, including methoxy, alcohol, aldehyde, and nitro groups.
Assuntos
Benzopiranos/química , Benzopiranos/síntese química , Carbono/química , Ciclização , Eletroquímica , Estrutura MolecularRESUMO
2,3-Disubstituted benzo[b]selenophenes have been prepared by the electrophilic cyclization of various 1-(1-alkynyl)-2-(methylseleno)arenes by Br2, NBS, I2, ICl, PhSeCl, PhSeBr, and Hg(OAc)2. This method tolerates a wide variety of functional groups, including alcohol, ester, nitrile, nitro, and silyl groups, and proceeds under exceptionally mild reaction conditions.