RESUMO
The Nazarov cyclization, a well-known method for the formation of cyclopentenones, mechanistically involves the 4π electrocyclization of a 1,4-pentadienyl cation, generated from cross-conjugated divinyl ketones. Recently, advances related to this cyclization, such as the incorporation of heteroatoms as well as the use of cyclopropanes as double bond equivalents have extended the scope of the original reaction. The modifications discussed in this review, which covers the years 2009-2013, have allowed the realization of both heteroatom- and homo-Nazarov cyclizations.
RESUMO
Two classes of compounds, thiocarbamates 1 and triazoles 2, have been identified as HIV RT RNase H inhibitors using a novel FRET-based HTS assay. The potent analogs in each series exhibited selectivity and were active in cell-based assays. In addition, saturable, 1:1 stoichiometric binding to target was established and time of addition studies were consistent with inhibition of RT-mediated HIV replication.
Assuntos
Fármacos Anti-HIV/química , Inibidores Enzimáticos/química , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Tiocarbamatos/química , Triazóis/química , Sequência de Aminoácidos , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Transferência Ressonante de Energia de Fluorescência , Ensaios de Triagem em Larga Escala , Humanos , Dados de Sequência Molecular , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Relação Estrutura-Atividade , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Pirimidinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologiaRESUMO
The preparation of alpha-methylbenzyl thioureas and their biological activity against varicella zoster virus is described. Several analogs demonstrated IC50s<0.1 microM and their SAR are discussed. These compounds represent a novel class of potent and selective nonnucleoside inhibitors of varicella zoster virus.
Assuntos
Antivirais/farmacologia , Herpesvirus Humano 3/efeitos dos fármacos , Tioureia/farmacologia , Antivirais/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tioureia/químicaRESUMO
The synthesis and biological activity of pyrimidotetrazin-6-ones against HCMV protease is described. The mechanism of action for these inhibitors is the oxidation of several cysteine residues to generate cross-linked enzyme.
