RESUMO
A versatile synthesis of 4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxylate esters has been developed which has lead to the identification of a new series of non-nucleoside inhibitors of human herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases.
Assuntos
Antivirais/síntese química , Inibidores Enzimáticos/síntese química , Furanos/síntese química , Herpesviridae/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico , Piridonas/síntese química , Antivirais/farmacologia , Química Farmacêutica/métodos , Citomegalovirus/enzimologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ésteres , Furanos/farmacologia , Herpesvirus Humano 3/enzimologia , Herpesvirus Humano 4/enzimologia , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Piridonas/farmacologia , Simplexvirus/enzimologiaRESUMO
A novel series of 2-aryl-2-hydroxyethylamine substituted 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides have been identified as potent antivirals against human herpesviruses. These compounds demonstrate broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, EBV, and VZV with high specificity compared to human DNA polymerases.
Assuntos
Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Etilaminas/farmacologia , Exodesoxirribonucleases/antagonistas & inibidores , Herpesviridae/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 4/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico , Piridinas/farmacologia , Proteínas Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/uso terapêutico , Ligação Competitiva , DNA Polimerase Dirigida por DNA , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Etilaminas/síntese química , Herpes Zoster/tratamento farmacológico , Herpesviridae/enzimologia , Humanos , Modelos Químicos , Piridinas/síntese química , Relação Estrutura-AtividadeRESUMO
A novel series of 4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides have been identified as potential antivirals against human herpesvirus infections resulting from human cytomegalovirus (HCMV), herpes simplex virus type 1 (HSV-1), and varicella-zoster virus (VZV). Compounds 10c and 14 demonstrated broad-spectrum inhibition of the herpesvirus polymerases HCMV, HSV-1, and VZV. High specificity for the viral polymerases was observed compared to human alpha polymerase. The antiviral activity of 10c and 14, as determined by plaque reduction assay, was comparable or superior to that of existing antiherpes drugs, ganciclovir (for HCMV) and acyclovir (for HSV-1 and VZV). Drug resistance to compound 14 correlated to point mutations in conserved domain III of the herpesvirus DNA polymerase, but these mutations do not confer resistance to existing nucleoside therapy. In addition, compound 14 maintained potent antiviral activity against acyclovir-resistant HSV-1 strains. Substitution to the pyridone nitrogen (N7) was found to be critical for enhanced in vitro antiviral activity.