RESUMO
HIV-1 integrase (IN), one of the essential enzymes in HIV infection, has been validated as a target for HIV treatment. While more than 20 drugs have been approved by the FDA to treat HIV/AIDS, only one drug, Raltegravir (1), was approved as an IN inhibitor. The rapid mutation of the virus, which leads to multidrug resistant HIV strains, presents an urgent need to find potent compounds that can serve as second-generation IN inhibitors. The pyrazolone scaffold, predicted by a computational modeling study using GS-9137(2) as a pharmacophoric model, has shown to inhibit the IN catalytic activities in low micromolar range. We have synthesized various analogs based on the pyrazolone scaffold and performed SAR studies. This paper will showcase the up-to-date result of this scaffold as a promising HIV-1 IN inhibitor.
Assuntos
Inibidores de Integrase de HIV/farmacologia , Pirazolonas/farmacologia , Catálise , Inibidores de Integrase de HIV/química , HIV-1/enzimologia , HIV-1/genética , Modelos Moleculares , Mutação , Pirazolonas/química , Relação Estrutura-AtividadeRESUMO
[reaction: see text] The "reverse polarity" or "umpolung" strategy for the total synthesis of aryl C-glycosides was developed in the context of the antibiotic (-)-griseusin B. Although a key reaction in a model sequence for the total synthesis produced two structurally divergent products, both were converted to the same advanced model intermediate that contains the complete carbon skeleton and (except for the extraneous oxygen substituent in the model series) the functional group pattern of the griseusins.
Assuntos
Glicosídeos/química , Glicosídeos/síntese química , Hidroquinonas/química , Modelos Moleculares , Estrutura Molecular , Naftoquinonas/síntese química , Naftoquinonas/química , EstereoisomerismoRESUMO
A series of adenosine 5'-phosphonate analogues were designed to mimic naturally occurring adenosine monophosphate. These compounds (1-5) were synthesized and evaluated in a cellular hepatitis C virus (HCV) replication assay. To improve cellular permeability and enhance the anti-HCV activity of these phosphonates, a bis(S-acyl-2-thioethyl) prodrug for compound 5 was prepared, and its cellular activity was determined. To elucidate the mechanism of action of these novel adenosine phosphonates, their diphosphate derivatives (1a-5a) were synthesized. Further nucleotide incorporation assays by HCV NS5B RNA-dependent RNA polymerase revealed that 2a and 3a can serve as chain terminators, whereas compounds 1a, 4a, and 5a are competitive inhibitors with ATP. Additional steady-state kinetic analysis determined the incorporation efficiency of 2a and 3a as well as the inhibition constants for 1a, 4a, and 5a. The structure-activity relationships among these compounds were analyzed, and the implication for nucleoside phosphonate drug design was discussed.
Assuntos
Antivirais/síntese química , Desoxiadenosinas/síntese química , Hepacivirus/efeitos dos fármacos , Organofosfonatos/síntese química , Antivirais/química , Antivirais/farmacologia , Linhagem Celular , DNA Viral/antagonistas & inibidores , DNA Viral/biossíntese , Desoxiadenosinas/química , Desoxiadenosinas/farmacologia , Desenho de Fármacos , Humanos , Organofosfonatos/química , Organofosfonatos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Replicação Viral/efeitos dos fármacosRESUMO
A series of 2,6,8-trisubstituted purine nucleoside libraries was prepared by parallel solid-phase synthesis using 8-bromoguanosine as a common synthetic precursor. Polystyrene-methoxytrityl chloride resin was linked to the N2 or O5' position of the guanosine analogues. 8-Bromoguanosine was derivatized at the C8 position via carbon-carbon bond formation. Nucleophilic aromatic substitution at C2 and/or C6 positions with various amines produced two series of purine nucleoside libraries with very diverse substitution.
Assuntos
Guanosina/análogos & derivados , Guanosina/química , Nucleosídeos de Purina/síntese química , Espectroscopia de Ressonância Magnética , Poliestirenos/química , Nucleosídeos de Purina/químicaRESUMO
Pyrrolopyrimidine nucleoside 1 was designed and synthesized as a potential mutagen for HCV. An in vitro HCV NS5B enzymatic assay indicated that pyrrolopyrimidine triphosphate acts as a CTP analog rather than a UTP analog. The SATE-prodrug of pyrrolopyrimidine monophosphate showed a weak inhibitory activity in an HCV replicon system (EC(50)=60 microM) and did not exhibit cytotoxicity (CC(50)>100 microM). Investigation of phosphorylation events using nucleoside kinases and LC-MS analysis revealed that the second phosphorylation step, from monophosphate ester to diphosphate ester, is unfavorable.
Assuntos
Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Mutagênicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Hepacivirus/fisiologia , Fosforilação , Replicação Viral/efeitos dos fármacosRESUMO
Nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. However, their low genetic barriers against resistance development, cross-resistance, and serious side effects can compromise the benefits of the two current drugs in this class (efavirenz and nevirapine). In this study, we report a novel and potent NNRTI, VRX-480773, that inhibits viruses from efavirenz-resistant molecular clones and most NNRTI-resistant clinical HIV-1 isolates tested. In vitro mutation selection experiments revealed that longer times were required for viruses to develop resistance to VRX-480773 than to efavirenz. RT mutations selected by VRX-480773 after 3 months of cell culture in the presence of 1 nM VRX-480773 carried the Y181C mutation, resulting in a less-than-twofold increase in resistance to the compound. A virus containing the double mutation V106I-Y181C emerged after 4 months, causing a sixfold increase in resistance. Viruses containing additional mutations of D123G, F227L, and T369I emerged when the cultures were incubated with increasing concentrations of VRX-480773. Most of the resistant viruses selected by VRX-480773 are susceptible to efavirenz. Oral administration of VRX-480773 to dogs resulted in plasma concentrations that were significantly higher than those required for the inhibition of wild-type and mutant viruses. These results warrant further clinical development of VRX-480773 for the treatment of HIV infection in both NNRTI-naive and -experienced patients.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa , Triazóis/farmacologia , Administração Oral , Alcinos , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/farmacologia , Linhagem Celular , Ciclopropanos , Cães , Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/genética , Humanos , Mutação , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/farmacocinética , Triazóis/uso terapêuticoRESUMO
A new series of 1,2,4-triazoles was synthesized and tested against several NNRTI-resistant HIV-1 isolates. Several of these compounds exhibited potent antiviral activities against efavirenz- and nevirapine-resistant viruses, containing K103N and/or Y181C mutations or Y188L mutation. Triazoles were first synthesized from commercially available substituted phenylthiosemicarbazides, then from isothiocyanates, and later by condensing the desired substituted anilines with thiosemicarbazones.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Inibidores Enzimáticos/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Nucleosídeos/farmacologia , Relação Estrutura-Atividade , Triazóis/síntese químicaRESUMO
A series of 9-(2'-beta-C-methyl-beta-d-ribofuranosyl)-6-substituted purine derivatives were synthesized as potential inhibitors of HCV RNA replication. Their inhibitory activities in a cell based HCV replicon assay were reported. A prodrug approach was used to further improve the potency of these compounds by increasing the intracellular levels of 5'-monophosphate metabolites. These nucleotide prodrugs showed much improved inhibitory activities of HCV RNA replication.