RESUMO
Several thieno[3,4-d]pyrimidine derivatives, including four hitherto unknown 2',3'-dideoxy- and 2',3'-dideoxy-2',3'-didehydro-C-nucleoside analogues of adenosine and inosine have been synthesized. When evaluated in cell culture experiments against human immunodeficiency virus, none of the tested compounds exhibited any significant antiviral effect, while two of them showed some cytotoxicity.
Assuntos
Adenosina/análogos & derivados , Antivirais/síntese química , Antivirais/farmacologia , Inosina/análogos & derivados , Pirimidinas/síntese química , Pirimidinas/farmacologia , Antivirais/química , HIV/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Pirimidinas/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.
Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Indóis/farmacologia , Ácidos Fosfínicos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Indóis/síntese química , Indóis/química , Macaca fascicularis , Masculino , Modelos Moleculares , Estrutura Molecular , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/química , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-AtividadeRESUMO
A novel series of 3-aryl-phospho-indole (API) non-nucleoside reverse transcriptase inhibitors of HIV-1 was developed. Chemical variation in the phosphorus linker led to the discovery of 3-phenyl-methyl-phosphinate-2-carboxamide 14, which possessed excellent potency against wild-type HIV-1 as well as viruses bearing K103N and Y181C single mutants in the reverse transcriptase gene. Chiral separation of the enantiomers showed that only R enantiomer retained the activity. The pharmacokinetic, solubility, and metabolic properties of 14 were assessed.