RESUMO
Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4'-chloromethyl-2'-deoxy-2'-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4'-modified-2'-deoxy-2'-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.
Assuntos
Antivirais/síntese química , Desoxicitidina/análogos & derivados , Desoxirribonucleosídeos/síntese química , Pró-Fármacos/síntese química , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/crescimento & desenvolvimento , Cricetulus , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/crescimento & desenvolvimento , Desoxicitidina/síntese química , Desoxicitidina/farmacologia , Desoxirribonucleosídeos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Testes de Sensibilidade Microbiana , Cultura Primária de Células , Pró-Fármacos/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/crescimento & desenvolvimento , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Falha de Tratamento , Replicação Viral/efeitos dos fármacos , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/crescimento & desenvolvimento , Zika virus/efeitos dos fármacos , Zika virus/crescimento & desenvolvimentoRESUMO
New modifications to the scaffold of previously reported HBV capsid assembly effectors such as BAY 41-4109, HAP-12 and GLS4 were explored. The anti-HBV activity in the HepAD38 system, and cytotoxicity profiles of each of the new compounds has been assessed. Among them, five new iodo- and bromo-heteroarylpyrimidines analogs displayed anti-HBV activity in the low micromolar range.
Assuntos
Antivirais/síntese química , Proteínas do Capsídeo/metabolismo , Vírus da Hepatite B/fisiologia , Pirimidinas/química , Animais , Antivirais/química , Antivirais/farmacologia , Proteínas do Capsídeo/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Células Hep G2 , Humanos , Piridinas/química , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Células Vero , Replicação Viral/efeitos dos fármacosRESUMO
The synthesis of novel series of sulfamoylbenzamides as HBV capsid assembly effector is reported. The structure was divided into five parts which were independently modified as part of our lead optimization. All synthesized compounds were evaluated for their anti-HBV activity and toxicity in human hepatocytes, lymphocytes and other cells. Additionally, we assessed their effect on HBV cccDNA formation in an HBeAg reporter cell-based assay. Among the 27 compounds reported, several analogs exhibited submicromolar activities and significant reduction of HBeAg secretion. Selected compounds were studied under negative-stain electron microscopy for their ability to disrupt the HBV capsid formation. Structures were modeled into a binding site recently identified in the HBV capsid protein for similar molecules to rationalize the structure-activity relationships for this family of compounds.