RESUMO
Friedel-Crafts amidoalkylation was achieved by oxidation of dialkylamides using persulfate (S(2)O(8)(2-)) in the presence of the visible light catalyst, Ru(bpy)(3)Cl(2), at room temperature, via a reactive N-acyliminium intermediate. Alternatively, mild heating of the dialkylamides and persulfate afforded a metal and Lewis acid-free Friedel-Crafts amidoalkylation. Alcohols and electron-rich arenes served as effective nucleophiles, forming new C-O or C-C bonds. In general, photocatalysis provided higher yields and better selectivities.
Assuntos
Compostos Organometálicos/química , Rutênio/química , Alquilação , Catálise , Luz , Oxirredução , Fotoquímica , Fotólise , Temperatura , TermogravimetriaRESUMO
Hepatitis C virus (HCV) infection has been recognized as the major cause of liver failure that can lead to hepatocellular carcinoma. Among all the HCV proteins, NS5B polymerase represents a leading target for drug discovery strategies. Herein, we describe our initial research efforts towards the identification of new chemotypes as allosteric NS5B inhibitors. In particular, the design, synthesis, in vitro anti-NS5B and in cellulo anti-HCV evaluation of a series of 1-oxo-1H-pyrido[2,1-b][1,3]benzothiazole-4-carboxylate derivatives are reported. Some of the newly synthesized compounds showed an IC(50) ranging from 11 to 23 µM, and molecular modeling and biochemical studies suggested that the thumb domain could be the target site for this new class of NS5B inhibitors.
Assuntos
Benzotiazóis/química , Hepacivirus/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Sítios de Ligação , Linhagem Celular , Simulação por Computador , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Terciária de Proteína , Software , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
The 6-desfluoroquinolones (6-DFQs) are anti-HIV agents that target Tat-mediated transcription. This particular mechanism of action makes this class of compounds very attractive for further structural investigations. Identification of the pharmacophore required for inhibition will ultimately result in the design of more selective analogues for use in combination therapy for the treatment of HIV infections. We have focused on the pyridone ring of the quinolone nucleus present in these compounds, designing new modifications to broaden the structure-activity relationship knowledge base. Herein, we present novel and very potent anti-HIV quinolones, most notably those bearing an amino or vinyl group at the N1 position. Attempts were made to determine the structural parameters necessary to impart potent anti-HIV activity to the vinyl derivatives.