RESUMO
Human lens epithelium-derived growth factor (LEDGF)/p75 plays an important role in the HIV life cycle by stimulating integrase (IN)-led viral DNA integration into cellular chromosomes. Mechanistic studies show the majority of IN inhibitors chelate magnesium ions in the catalytic active site, a region topologically distant from the LEDGF/p75 binding site. Compounds disrupting the formation of LEDGF/p75 and IN complexes serve as a novel mechanistic approach different from current antiretroviral therapies. We previously built pharmacophore models mimicking LEDGF/p75 residues and identified four classes of LEDGF/p75-IN inhibitors. Substructure and similarity searches yielded additional LEDGF/p75-IN inhibitors containing an acylhydrazone moiety. The most potent of the acylhydrazones inhibited LEDGF/p75-IN interaction with an IC(50) value of 400nM. We explored structure-activity relationships (SAR) and identified new acylhydrazones, hydrazines, and diazenes as lead molecules for further optimization. Two lead LEDGF/p75-IN inhibitors showed antiviral activity.
Assuntos
Inibidores de Integrase de HIV/química , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos/química , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Integrase de HIV/química , Integrase de HIV/genética , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Humanos , Hidrazinas/química , Hidrazonas/química , Imidas/química , Simulação de Acoplamento Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-AtividadeRESUMO
The methanol extract of the dried leaves of Abies webbiana was evaluated for antimicrobial activity. The methanol extract showed a broad spectrum of antibacterial activity.
Assuntos
Abies , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Aspergillus niger/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Folhas de PlantaRESUMO
During the determination of LD50 values of extracts of Abies webbiana, it was observed that the methanol extract (MEAW) produces sedation of animals. This led to investigation of the effect of MEAW on sleeping time in mice. When various doses of the methanol extract (100, 150, and 200 mg/kg body weight) were administered alone, no hypnotic activity was observed. However, these exhibited significant synergistic effects (P < 0.001) at those dose levels in mice when administered prior to the administration of standard sedatives (pentobarbitone sodium: 50 mg/kg and diazepam: 6 mg/kg, respectively). In addition anti-inflammatory effects of methanol, chloroform, and petroleum ether extracts of Abies webbiana leaves in rats were performed to assess scientific validity of the medicinal claim of Indian folk medicine. The effects of leaf extracts (methanol, chloroform, and petroleum ether) against inflammation were studied by carrageenan-induced paw edema model in rats. The methanol extract (400 mg/kg p.o.) of leaves of Abies webbiana showed the best significant anti-inflammatory activity as compared to that of diclofenac sodium (150 mg/kg p.o.). The LD50 values of methanol, chloroform, and petroleum ether extracts were found to be 986, 1387, and > 3200 mg/kg, respectively. Thus, the therapeutic index of methanol extract may be favorable to open a new vista on combination therapy of hypnotics and may also against inflammation.