RESUMO
A small focused library of 18 compounds incorporating the motif 1,3-(N,N'-dibenzyl)diamino-2-propanol has been synthesized, using adapted synthetic methodologies. These series of compounds were evaluated for their in vitro anti-HIV activity on infected MT4 cells (syncytium formation observation). Some of the new synthesized compounds show potent anti-HIV activities. EC50 values for compounds (31, 40, 34, 37 and 46) range from 0.1 to 1 microM. In order to determine at which level these new derivatives interfere with the HIV replicative cycle, inhibition assays on recombinant HIV protease and HIV integrase have been performed. None of the compounds were found active on these two enzymatic targets. Experiments are in progress in order to identify their biological target within the HIV replicative cycle.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/química , Linhagem Celular , Células Gigantes , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Replicação Viral/efeitos dos fármacosRESUMO
A series of new anti-HIV derivatives containing a novel alpha-thiophenoxyhydroxyethylamide core have been synthesized, using S-phenylbenzenethiosulfonate as the thiosulfenylating reagent. Some of the new synthesized compounds (1a, 1c, 1g, 1i, 1j and 1l) inhibited HIV replication in cell culture assays (syncytia formation) with effective concentrations (EC(50)) ranging from 0.1-1 microM. Incorporation of thiophenoxy substitution within various pseudomimetic peptide backbones provided a series of highly potent HIV inhibitors.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Alcanos/síntese química , Alcanos/farmacologia , Amidas/síntese química , Amidas/farmacologia , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Replicação Viral/efeitos dos fármacosRESUMO
We report the synthesis and the anti-HIV activities of new C2-symmetrical and achiral N1,N3-dibenzyl-2-hydroxy-propane isosteres. Some of them showed significant inhibitory activity with respect to HIV-infected MT4 cells (compound 6a and 7a, IC50 = 0.1 microM). These new structurally simple compounds represent new synthons which can be suitable for combinatorial chemistry purposes.
