RESUMO
Recently we reported benzohydroxamic acids (BHAs) as potent and selective inhibitors of hepatitis C virus (HCV) replicon propagation. In this work 12 pyridine hydroxamic acids (PHAs) were synthesized and tested in full-genome replicon assay. It was found that PHAs possessed very similar anti-HCV properties compared to BHAs. Both classes of hydroxamic acids caused hyperacetylation of α-tubulin pointing to inhibition of histone deacetylase 6 (HDAC6) as part of their antiviral activity. The tested compounds did not inhibit the growth of poliovirus, displaying high selectivity against HCV.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Piridinas/química , Antivirais/química , Linhagem Celular Tumoral , Regulação da Expressão Gênica/efeitos dos fármacos , Desacetilase 6 de Histona , Histona Desacetilases/genética , Humanos , Ácidos Hidroxâmicos/química , Estrutura Molecular , Poliovirus/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos , VírusRESUMO
New oxime-containing acyclic nucleoside phosphonates 9-{2-[(phosphonomethyl)oximino]ethyl}adenine (1), -guanine (2) and 9-{2-[(phosphonomethyl)oximino]propyl}adenine (3) with wide spectrum activity against different types of viruses were synthesized. The key intermediate, diethyl aminooxymethylphosphonate, was obtained by the Mitsunobu reaction. Modified conditions for the by-product separation (without chromatography and distillation) allowed us to obtain 85% yield of the aminooxy intermediate. The impact of DBU and Cs2CO3 on the N(9)/N(7) product ratio for adenine and guanine alkylation was studied. A convenient procedure for aminooxy group detection was found. The synthesized phosphonates were tested and they appeared to display moderate activity against different types of viruses (HIV, herpes viruses in cell cultures, and hepatitis C virus in the replicon system) without toxicity up to 1000 µM.
Assuntos
Antivirais/síntese química , Nucleosídeos/síntese química , Organofosfonatos/síntese química , Oximas/síntese química , Antivirais/química , Antivirais/farmacologia , Humanos , Nucleosídeos/química , Nucleosídeos/farmacologia , Organofosfonatos/química , Organofosfonatos/farmacologia , Oximas/química , Oximas/farmacologia , Viroses/tratamento farmacológico , Vírus/efeitos dos fármacosRESUMO
A diverse collection of 40 derivatives of benzohydroxamic acid (BHAs) of various structural groups were synthesized and tested against hepatitis C virus (HCV) in full-genome replicon assay. Some of these compounds demonstrated an exceptional activity, suppressing viral replication at sub-micromolar concentrations. The compounds were inactive against key viral enzymes NS3, and NS5B in vitro assays, suggesting host cell inhibition target(s). The testing results were consistent with metal coordination by the BHAs hydroxamic group in complex with a target(s). Remarkably, this class of compounds did not suppress poliomyelitis virus (PV) propagation in RD cells indicating a specific antiviral activity of BHAs against HCV.