RESUMO
DOPA decarboxylase (DDC) is responsible for the decarboxylation of l-DOPA and related aromatic amino acids and correlates closely with a number of clinical disorders. Sanguinarine, a natural quaternary benzophenanthridine alkaloid (QBA), was reported to be inhibitor of rat DDC and possessed a different inhibitory mechanism. In this study, several natural QBAs were assayed as human DDC inhibitors for the first time. A series of 5-methyl phenanthridium derivatives that contain the basic core structure of QBAs were also synthesized and evaluated as human DDC inhibitors. The title compounds still possessed DDC inhibitory potential. Among the synthesized compounds, 2-hydroxyl-8-methoxy-5-methylphenanthridinium chloride (11k) showed good inhibitory activity with an IC50 value of 0.12mM. Preliminary structure-activity relationship indicated that DDC inhibitory potential of 5-methyl phenanthridium derivatives correlated with the π-electro densities on CN double bond of iminium cation. The hydroxyl group on compound 11k possibly contributed to the formation of hydrogen bond between DDC and the inhibitor.
Assuntos
Inibidores das Descarboxilases de Aminoácidos Aromáticos/síntese química , Inibidores das Descarboxilases de Aminoácidos Aromáticos/farmacologia , Fenantridinas/síntese química , Fenantridinas/farmacologia , Animais , Inibidores das Descarboxilases de Aminoácidos Aromáticos/química , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Fenantridinas/química , RatosRESUMO
A series of isoquinoline alkaloids including tetrahydroprotoberberines, N-methyl tetrahydroprotoberberines and protoberberines were facile synthesised with protopines as the starting material. All compounds were evaluated for their antibacterial activities against four pathogenic bacteria Escherichia coli, Staphyloccocus aureus, Staphylococcus gallinarum and Salmonella choleraesuis. Experimental results indicated that protoberberines were the most active compounds to the target bacteria among the tested alkaloids. It was suggested that planar molecule with high aromatisation level (e.g. coptisine 5 and berberine 6) or a positive charge of the molecules (e.g. N-methyl tetrahydroprotoberberines 11 and 12) had a positive influence on the antibacterial effects.