RESUMO
A series of 13 hydroxylated 2-arylnaphthalenes have been synthesized and evaluated as HIV-1 integrase inhibitors. 7-(3,4,5-trihydroxyphenyl)naphthalene-1,2,3-triol 1c revealed chemical instability upon storage, leading to the isolation of a dimer 5c which was also tested. In the 2-arylnaphthalene series, all compounds were active against HIV-1 IN with IC50's within the 1-10 microM range, except for 1c and 5c which displayed submicromolar activity. Antiviral activity against HIV-1 replication was measured on 1b-c and 5c. Amongst the tested molecules, only 5c was found to present antiviral properties with a low cytotoxicity on two different cell lines.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , Naftalenos/química , Naftalenos/farmacologia , Fármacos Anti-HIV/síntese química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Integrase de HIV/síntese química , HIV-1/enzimologia , Humanos , Naftalenos/síntese químicaRESUMO
Following the discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors, a plethora of new molecules have been published leading to four drugs under clinical trial. In an attempt to rationally design new dimeric diketoacids (DKAs) targeting two divalent metal ions on the active site of IN, potent inhibitors against purified IN were found with varied selectivity for strand transfer. In this context, we designed and synthesized a new series of catechol-DKA hybrids. These compounds presented micromolar anti-integrase activities with moderate antiviral properties.
Assuntos
Ácidos/química , Ácidos/farmacologia , Catecóis/química , Desenho de Fármacos , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Ácidos/síntese química , Catálise , Dimerização , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , HIV-1/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The interactions with divalent cations of 4-phenyl-4-oxo-2-hydroxybuten-2-oic acid (benzoylpyruvic acid (BPA)), the pharmacophore of HIV-1 integrase inhibitors, were investigated using spectroscopic tools. In the absence of the enzyme, a 2:2 metal-ligand complex was characterized with an intermetallic distance of 4-6 A. Molecular modeling allowed us to propose a compatible structure for the metal-ligand complex. BPA does not inhibit the reactions catalyzed by HIV-1 IN, emphasizing the importance of the aromatic ring substitution in the antiviral activity.
Assuntos
Integrase de HIV/química , Magnésio/química , Manganês/química , Ácido Pirúvico/análogos & derivados , Ácido Pirúvico/química , Cátions Bivalentes/química , Espectroscopia de Ressonância de Spin Eletrônica , Ligantes , Espectrometria de Massas , Modelos Moleculares , Estrutura MolecularRESUMO
A series of hydroxylated 3-hydroxycoumarins was synthesised by the reaction of 3-aryl-2-hydroxypropenoic derivatives with boron tribromide. They were evaluated for their ability to scavenge the 2,2-diphenyl-1-picrylhydrazyl radical, the superoxide anion radical, the hydroxyl radical and the peroxynitrite anion and to inhibit copper-induced human LDL peroxidation. The physicochemical results were in accordance to establish the compounds hydroxylated on C-6 and C-7 positions as the most active of the series with antioxidant potencies comparable to those of quercetin and vitamin C. These compounds form o- and p-quinonoid derivatives upon radical scavenging and may serve as new lead compounds for pharmacological investigations.
