RESUMO
We have previously reported the synthesis and evaluation of potent anti-human immunodeficiency virus compounds based on beta-D-d4T analogues bearing a tether attached at the C-5 position and their beta-L-counterparts. Initial study revealed a requirement for an alkyl side-chain with an optimal length of 12 carbons for a weak antiviral activity. As a continuation of that work, we have now prepared the corresponding phosphoramidate derivatives as possible membrane-permeable prodrugs. Phosphorochloridate chemistry gave the target phosphoramidates which were tested for anti-human immunodeficiency virus type 1 activity; unfortunately, they were devoid of anti-HIV activity.
Assuntos
Amidas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Didesoxinucleosídeos/química , Ácidos Fosfóricos/química , Uridina Monofosfato/análogos & derivados , Fármacos Anti-HIV/química , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Uridina Monofosfato/químicaRESUMO
Selected for their expected ability to inhibit HIV replication, a series of eight heterodimers containing a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and an Integrase Inhibitor (INI), bound by a linker, were designed and synthesized. For the NRTIs, d4U, d2U and d4T were chosen. For the INIs, 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (6) and 4-(3,5-dibenzyloxyphenyl)-2,4-dioxobutyric acid (9) (belonging to the beta-diketo acids class) were chosen. The conjugation of the two different inhibitors (NRTI and INI) was performed using an amino acid (glycine or beta-alanine) as a cleavable linker.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores de Integrase de HIV/química , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Expected for their ability to inhibit HIV replication, four heterodimers with a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) bound by a linker arm were designed and synthesized. For the NRTIs, d4U, d2U, d4T and 5'-O-acetyl-5-(3-hydroxypropynyl)d2U were chosen. For the NNRTI, a Trovirdine Analogue (belonging to the phenethylthiazolylthiourea class) was chosen. The conjugation of the two different inhibitors (NRTI and NNRTI) was performed using the succinyl-glycine moiety as a spontaneously cleavable linker.
