RESUMO
As a continuation of our previous work, which resulted in the identification of a new hit compound as an HIV-1 integrase inhibitor, three novel series of salicylic acid derivatives were synthesized using three versatile and practical synthetic strategies and were assayed for their capacity to inhibit the catalytic activity of HIV-1 integrase. Biological evaluations revealed that some of the synthesized compounds possess good inhibitory potency in enzymatic assays and are able to inhibit viral replication in MT-4 cells at low micromolar concentrations. Finally, docking studies were conducted to analyze the binding mode of the synthesized compounds within the DNA binding site of integrase in order to refine their structure-activity relationships.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A novel compound inhibiting HIV-1 integrase has been identified by means of virtual screening techniques. A small family of structurally related molecules has been synthesized and biologically evaluated with some of the compounds possessing micromolar activity both in enzymatic and cellular assays.
Assuntos
Fármacos Anti-HIV/química , Inibidores de Integrase de HIV/química , Integrase de HIV/química , HIV-1/efeitos dos fármacos , Rodanina/química , Tiobarbitúricos/química , Tioidantoínas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Humanos , Rodanina/síntese química , Relação Estrutura-Atividade , Tiobarbitúricos/síntese química , Tioidantoínas/síntese químicaRESUMO
Heck-type 4-exo-trig cyclization of linear 2-enol triflate-1,5-hexadienes provides functionalized methylene cyclobutanes. Intramolecular palladium coordination can initiate beta-hydride elimination leading to 1,2-dimethylene cyclobutane derivatives, which are obtained with high selectivity if substrates having a geminal diphenyl group at Calpha are used. In parallel, formal 5-endo-trig cyclization and beta-hydride elimination form 1-methylene cyclopent-2-en derivatives.
