Design, Synthesis And Biological Evaluation Of Novel Quinolin-2(1H)-one Derivatives As Potential Chitin Synthase Inhibitors

Chitin is a major and essential component of the fungal cell wall. It was formed by UDP-N-acetyl-D-glucosamine (UDP-GlcNac) using chitin synthases (CHS) as catalyst, which is absent in mammalian cells. Thus, CHS is a very promising target for designing antifungal agents. Base on the structural characteristics of some reported chitin synthase inhibitors, we designed and synthesized a series of quinoline-2(1H)-one derivatives, whose structure roughly resemble that of polyoxin B, as chitin synthase inhibitors, and tested their inhibition activity against the Chitin Synthase using non-radioactive high-throughput detection method, and their antifungal and antibacterial activity were evaluated as well. The assays indicated that some of these compounds showed good inhibitory activity against chitin synthase. The piperazine derivatives10a and10c exhibited excellent inhibitory activity with IC50values of0.10mM and0.15mM, respectively. They are better than that of Polyoxin B whose IC50value is0.18mM. The tartaric derivatives exhibited relatively weak inhibitory activity. Among them, the compound9r showed the best inhibitory activity with IC50values of0.36mM. All the target compounds were screened for their antifungal and antibacterial activity in vitro. Some of them showed equivalent or superior inhibitory activity in comparison with the reference drugs. The assays also indicated that there is a positive correlated between the antifungal activity and the inhibitory activity against chitin synthase, and indicate that the activity against fungi is better than that of bacterial. The main work was summarized as following:1、Synthesis of5-amino-3,4-dihydroquinolin-2(1H)-one.1,3-cyclohexanedionoe as the starting material, via multistep reactions about ammoniated, Michael addition, cyclization, oximation, benzoyl, Semmler-wolffaromatization and finally hydrolysis, the key intermediate5-amino-3,4-ihydroquinolin-2(1H)-one was obtain. The total yield is6.4%.2、Synthesis of quinolin-2(1H)-one piperazine derivatives:The intermediate5-amino-3,4-dihydroquinolin-2(1H)-one reacted with bis(2-bromoethyl)amine hydrobromide to give the piperazine product, which reacted with epichlorohydrin to afford ethylene oxide compound. Then the ethylene oxide compound was reacted with substituted aromatic amine or aliphatic amine under solvent-free conditions to prepare the corresponding piperazine derivatives.3、Synthesis of quinolin-2(1H)-one tartaric derivatives:L-tartaric acid as raw material, via multistep reactions about esterification, protected hydroxy, hydrolysis, combination with a series of substituted aryl or heterocyclic amine, hydrolysis, a series of carboxylic acid intermediates were afforded. The carboxylic acid intermediate combined with5-amino-3,4-dihydroquinolin-2(1H)-one, via deprotection to obtain tartaric derivative.4、Synthesis of quinolin-2(1H)-one alanine amides derivatives:The intermediate5-amino-3,4-dihydroquinolin-2(1H)-one was converted to the amino compound, via multistep reactions about ethyl protection, hydroxyethylation, condensation and deprotected Boc group. The amino compound combined with a series of substituted benzoic acid or aromatic heterocyclic acid to afford alanine amides derivatives.5、For some target compounds, we tested their Chitin Synthase inhibitory activity. The assays indicated that the piperazine derivatives showed better inhibitory activity against chitin synthase than that of the tartaric acid derivatives.6、All the target compounds were screened for their in vitro antimicrobial and antifungal activity against six strains of bacteria and five fungi using the standard two folds serial dilution method in96-well microtest plates. Activity screening results showed that the piperazine derivatives and alanine amides derivatives showed better antimicrobial activity than that of the tartaric acid derivatives.