RESUMO
Based on molecular docking analysis of earlier results, we designed a series of 2,5-disubstituted furans/pyrroles (5a-h) as HIV-1 entry inhibitors. Compounds were synthesized by Suzuki-Miyaura cross coupling, followed by a Knoevenagel condensation or Wittig reaction. Four of these compounds were found to be effective in inhibiting HIV-1 infection, with the best compounds being 5f and 5h, which exhibited significant inhibition on HIV-1(IIIB) infection at micromolar levels with low cytotoxicity. These compounds are also effective in blocking HIV-1 mediated cell-cell fusion and the gp41 six-helix bundle formation, suggesting that they are also HIV-1 fusion inhibitors targeting gp41 and have potential to be developed as a new class of anti-HIV-1 agents.
Assuntos
Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/química , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirróis/química , Pirróis/farmacologia , Desenho de Fármacos , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Proteína gp41 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/síntese química , Infecções por HIV/tratamento farmacológico , Humanos , Pirróis/síntese químicaRESUMO
The transprotection of N-Fmoc-cysteine containing di- and tripeptides possessing a free SH group to produce the corresponding S-Fm-cysteine di- and tripeptides bearing a free amino group is accomplished efficiently with DBU in dry THF. The N-Fmoc to S-Fm transformation mechanism is discussed. S-Fm-Cysteine di- and tripeptides readily form amide bonds on coupling with N-(Pg-α-aminoacyl)benzotriazoles and N-(Pg-α-dipeptidoyl)benzotriazoles to give larger peptides.
