RESUMO
Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LEL-HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. The prepared compounds were tested for their inhibitory potency by means ofa fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity relationships could be derived. Optimization was successful, leading to 3g, identified as the most potent compound (69 % inhibition). Experiments with viral particles revealed that there might be additional HCV infection reducing mechanisms.
Assuntos
Antígenos CD/metabolismo , Terfenadina/síntese química , Terfenadina/farmacologia , Proteínas do Envelope Viral/antagonistas & inibidores , Acilação/efeitos dos fármacos , Anticorpos Antivirais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Testes de Neutralização , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Terfenadina/química , Tetraspanina 28 , Proteínas do Envelope Viral/metabolismo , Vírion/efeitos dos fármacosRESUMO
A new synthesis of carboxyterfenadine (4), based on the conversion of a alpha-halo-alkylarylketone into the corresponding substituted 2-arylalkanoic ester, is described. The enantioselective synthesis of its two bioisosteric tetrazole analogs together with preliminary biological results are reported.
