RESUMO
A series of hydroxamates (4a-4l) were prepared from p-aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds (4f &4l) were found to inhibit HDAC8 at concentrations (IC50) less than 20µM.
Assuntos
Ácido 4-Aminobenzoico/química , Ácido 4-Aminobenzoico/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Cristalografia por Raios X , Desenho de Fármacos , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Relação Estrutura-AtividadeRESUMO
Thiosemicarbazones of p-aminobenzoic acid (PABA) were synthesized and tested for their antimicrobial and anticancer activity. Hydroxamate derivatives 4a-4l were found to have better antimicrobial and anticancer activity than their acid counterpart. Compound 4d was found to have good antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Vibrio cholerae, and Bacillus subtilis with IC(50) value of about 1 µM. Compound 4f showed potent antifungal activity against Candida albicans (IC(50) = 1.29 µM) and compound 4h showed potent anticancer activity (IC(50) = 0.07 µM).
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologia , para-Aminobenzoatos , Amidoidrolases/antagonistas & inibidores , Anti-Infecciosos/química , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HT29 , Humanos , Ácidos Hidroxâmicos/química , Testes de Sensibilidade Microbiana/métodos , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/químicaRESUMO
The present study was designed to evaluate the anti-inflammatory and antiarthritic activity of the new synthetic thienopyridine analogs. The anti-inflammatory activity of thienopyridines was assayed by using carrageenan; dextran and arachidonic acid induced paw edema models (acute), cotton pellet granuloma model (Sub acute) and Freund's complete adjuvant induced arthritis (chronic) in experimental rats. The compounds BN-4, BN-14 and BN-16 have shown significant inhibition of edema in carrageenan and arachidonic acid induced paw edema model at a dose of 100mg/kg compared to the dextran induced paw edema model and also showed significant inhibition in granuloma tissue formation and Freund's complete adjuvant induced arthritis in experimental rats. These thienopyridine analogs also inhibited the proinflammatory mediators such as Tumor necrosis factor (TNF)-α, Interleukin (IL)-1ß and Nitric Oxide (NO) in Lipopolysaccharide (LPS) challenged murine macrophages. Ulcerogenecity study results revealed less ulcerogenic potential of BN-4, BN-14 and BN-16 compared to nonsteroidal anti-inflammatory drug (NSAID) indomethacin in rats. In conclusion, the new thienopyridine analogs were promising for the potential use as anti-inflammatory agents for both acute and chronic inflammatory disorders with low toxic effects.