RESUMO
Three 7-fluoro-7-deaza-2-aminopurine nucleoside derivatives were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).
Assuntos
Antivirais/síntese química , Nucleosídeos de Purina/síntese química , Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Nucleosídeos de Purina/química , Nucleosídeos de Purina/farmacologiaRESUMO
9-Deazaguanosine and the alpha and beta anomers of its 2'-C-methyl counter part, have been synthesized and evaluated against a broad range of RNA viruses, including hepatitis C virus.
Assuntos
Antivirais/síntese química , Guanosina/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Flavivirus/efeitos dos fármacos , Guanosina/síntese química , Guanosina/química , Guanosina/farmacologia , Hepacivirus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as the sugar moiety was synthesized and evaluated as a potential inhibitor of several virus replication.
Assuntos
Adenosina/análogos & derivados , Antivirais/síntese química , Adenosina/síntese química , Adenosina/química , Adenosina/farmacologia , Antivirais/química , Antivirais/farmacologiaRESUMO
A series of novel 4-fluoro-1H-pyrazole-3-carboxamide nucleoside analogues were synthesized and evaluated as potential inhibitors of RNA virus replication, including hepatitis C virus (HCV).
Assuntos
Antivirais/síntese química , Ribavirina/análogos & derivados , Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacosRESUMO
RNA viruses are the agents of numerous widespread and often severe diseases. Their unique RNA-dependent RNA polymerase (RDRP) is essential for replication and, thus, constitutes a valid target for the development of selective chemotherapeutic agents. In this regard, we have investigated sugar-modified ribonucleoside analogues as potential inhibitors of the RDRP. Title compounds retain 'natural' pyrimidine bases, but possess a beta-methyl substituent at the 2'-position of the D- or L-ribose moiety. Evaluation against a broad range of RNA viruses, either single-stranded positive (ssRNA+), single-stranded negative (ssRNA-) or double-stranded (dsRNA), revealed potent activities for D-2'-C-methyl-cytidine and -uridine against ssRNA+, and dsRNA viruses. None of the L-enantiomers were active. Moreover, the 5'-triphosphates of the active D-enantiomers were found to inhibit the bovine virus diarrhoea virus polymerase. Thus, the 2'-methyl branching of natural pyrimidine ribonucleosides transforms physiological molecules into potent, broad-spectrum antiviral agents that merit further development.
Assuntos
Antivirais/farmacologia , Nucleosídeos de Pirimidina/farmacologia , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/fisiologia , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Linhagem Celular , Cricetinae , Cães , Haplorrinos , Humanos , Estrutura Molecular , Nucleosídeos de Pirimidina/química , Relação Estrutura-AtividadeRESUMO
2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/classificação , Alquilação , Aminação , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/classificação , Linhagem Celular , Flúor/química , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Mutação/genética , Nucleosídeos/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
Dihydro-alkoxy-benzyl-oxopyrimidines (DABOs) are a family of potent NNRTIs developed in the past decade. Attempts to improve their potency and selectivity led to thio-DABOs (S-DABOs), DATNOs, and difluoro-thio-DABOs (F(2)-S-DABOs). More recently, we reported the synthesis and molecular modeling studies of a novel conformationally constrained subtype of the S-DABO series characterized by the presence of substituents on the methylene linkage connecting the pyrimidine ring to the aryl moiety (Mai, A., et al. J. Med. Chem. 2001, 44, 2544-2554). Now we report the computer-aided design, synthesis, and biological evaluation of four new DABO prototypes (5-alkyl-2-cyclopentylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones, F(2)-NH-DABOs) in which the sulfur atom of the related F(2)-S-DABOs is replaced by an amino group. For these studies, we used as a reference model the cocrystallized MKC-442/RT complex. Docking studies with Autodock of the newly designed F(2)-NH-DABOs on the ligand-derived RT confirmed the findings previously described for the F(2)-S-DABOs. The F(2)-NH-DABO binding mode resembles that reported for F(2)-S-DABOs, with the difference that the NH moiety at the C-2 position represents a new anchor site for ligand/enzyme complexation. The predicted inhibition constant (K(i)) values by the internal scoring function of Autodock, and the predicted IC(50) values by the application of a VALIDATE II/HIV-RT model strongly suggested the synthesis of the designed amino-DABOs. F(2)-NH-DABOs were shown to be highly active in both anti-RT and anti-HIV biological assays with IC(50) and EC(50) comparable with that of the reference compound MKC-442. Interestingly, 2-cyclopentylamino-6-[1-(2,6-difluorophenyl)ethyl]-3,4-dihydro-5-methyl pyrimidin-4(3H)-one (9d) was active against the Y181C HIV-1 mutant strain at submicromolar concentration, with a resistance value similar to that of efavirenz, the last FDA-approved NNRTI for AIDS therapy, and 2-fold lower than that of its 2-cyclopentylthio counterpart 8d. The introduction in 9d of a new anchor point (pyrimidine C-2 NH group), with the formation of a new hydrogen bond with Lys101, could compensate for the lack of positive hydrophobic ligand/NNBP interactions due to the Tyr181 to Cys181 mutation.