Synthesis And Antibacterial Activities Research Of N-O-Hydroxyphenyl-Substituted Amino Acid Derivatives

In 1998, McMurry from American Tufts University discovered that triclosan killed the bacterium by blocking the synthesis of fatty acid, which proved that the FabI gene of acyl-ACP reductive enzyme (ENR) was the essential target for the first time. A lot of experiments were done afterward, which indicated that"2-hydroxyphenyl, 2-hydroxy-halophenyl"were the key structures of triclosan and its analogues that can kill the pathogenic germs. So"2-hydroxyphenyl, 2-hydroxy-halophenyl"were thought to be the core unit of antibiotic structure design.According to the recent studies, active units can change their molecular properties,boost up their effects and selectivities to the target cell after linking amino acids, and this kind of structures also have a stronger permeance to the films and a higher biological usage. So this work is wildly applied in the drug molecule design and synthesis research.A series of N-(2-hydroxyphenyl)-amino acids derivatives were designed and synthesized based on the key unit of"2-hydroxyphenyl, 2-hydroxy-halophenyl".1."2-hydroxyphenyl, 2-hydroxy-halophenyl"linked amino acids directly N-(2-hydroxyphenyl)-glycine ethyl ester was obtained from 2-amino-phenol and bromo-acetic acid ethyl ester via N-alkylation, then the ester was hydrolyzed under the base condition to produce N-(2-hydroxyphenyl)-glycine. On the other hand, the above compounds also can be gained by Ullmann reaction, and the catalysis of amino acids with Cu+ was proved in this reaction.2."2-hydroxyphenyl, 2-hydroxy-halophenyl"linked amino acids with methylene Salicylaldehyde and halo-salicylaldehyde were condensed with amino acids in the presence of sodium hydroxide to obtain amino acids Schiff base, which were reduced by NaBH4 to produce N-(2-hydroxylbenzyl)-amino acids and N-(2-hydroxyl-halobenzyl)-amino acids respectively. The condensation reaction may be much faster if the amino acids have hydrophobic small R group rather than the hydrophilic and big ones, such as Gly.. The condensation reaction would be more active with the halo-salicylaldehyde, especially with the 3,5-dibromo-salicylaldehyde.3."2-hydroxyphenyl, 2-hydroxy-halophenyl"linked amino acids with N-methyl-acetamide [N'-(2-Hydroxy-benzoyl)-hydrazino]-acetic acid ethyl ester was obtained from 2-hydroxy-benzoic acid methyl ester via hydrazination and N-alkylation, then the ester was hydrolyzed to produce [N'-(2-Hydroxy-benzoyl)-hydrazino]-acetic acid.Meanwhile, the antibacterial activities of most compounds were tested, and the relationships between antibacterial activities and structures also were discussed.