RESUMO
The structure-activity relationships (SARs) of acylthiocarbamates (ATCs), a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors, have been expanded. Sixty-six new analogues were prepared by parallel solution-phase synthesis. In general, the potency of new ATCs was better than that of the first series and O-[2-phthalimidoethyl] 4-chlorophenyl(3-nitrobenzoyl) thiocarbamate turned out to be the most potent ATC so far synthesized (EC(50)=1.5nM). Several ATCs were active at micromolar concentrations against HIV-1 strains carrying the RT Y181C mutation and one of them was also moderately active against the K103R variant. Docking simulations were carried out to rationalize the most relevant SARs.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Tiocarbamatos/síntese química , Simulação por Computador , HIV-1/efeitos dos fármacos , HIV-1/genética , Modelos Moleculares , Mutação de Sentido Incorreto , Ligação Proteica , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Tiocarbamatos/farmacologiaRESUMO
In the crystal structure of the novel acylthiocarbamate derivative O-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl] N-(4-methylphenyl)-N-(3-nitrobenzoyl)thiocarbamate, C25H19N3O6S, intra- and intermolecular pi-pi interactions occur between the phthalimide and N-benzoyl moieties. The partial atomic charges, calculated by ab initio methods, are consistent with the observed structure.
