The Study Of Synthesis Of Tetronic Acid Derivatives And Their Antibacterial Activity

Dug resistance of bacterias induced by clinical long-term abuses of antibiotics is a major problem in today's clinical treatment of infectious diseases. As a result, developing new innovative antimicrobial agents with new mechanisms and targets has become the most important way to combat drug resistance, even turn into a hot research topics.Tetronic acid derivatives are a serious of five-lactone structural compounds with antibacterial, antioxidant, anti-tumor, anti-inflammatory. Now,they are antibacterial lead compounds with great potential. In the process of bacterial cell wall synthesis, they can inhibit the enzyme activity of Mur to kill the bacterials. Five-lactone ring were employing widely as an important intermediates in synthesis because of its high reactivity.MurB is composed of one hydrophilic domain and two hydrophobic domains. Hydrophilic domain, as a catalytic center, catalyze UDP-Glc-NAc-enolpyruvate FAD and NADPH to generate UDP-MurNAc in peptidoglycan synthesis. According to Complex crystal structures of MurB enzyme-tetronic acid reported by Le Gall in 2007, we design and synthesis 24 tetronic acid derivatives, 20 of which are 3-aryl substituted and 4 are 3-alkyl substituted.According to the structural features of the designed tetronic acids, we develop a route based on aromatic acid andα-bromo esters through esterification, Dieckmannester condensation reaction, successfully synthesis 20 3-aryl substituted derivatives, the Yield of which are about 42.3% to 83%. Their structures are confirmed by IR, MS, 1H NMR, 13C NMR. At the same time, we designed a method and optimized each step to make 3-aryl substituted tetronic acids, which is on the basis of acetoacetate through alkyl substitution, bromide substitution, cyclization, Which was used to synthesis 3-alkyl substituted tetronic acid with the Yield of 38% to 43%. Their structures are also confirmed by IR, MS, 1H NMR, 13C NMR.The 24 compounds were studied with E. coli (ATCC 25922) and saphylococcus aureus(ATCC 25923) by mircoduliton method in vitro, then obtained MIC values. We found DT-24 has the weakest activity against E. Coli, DT-1, DT-3, DT-6, DT-7, DT-10, DT-11, DT-13's activities followed by (MIC = 32), DT-15 and DT-17 the best (MIC = 8), which revealed that tested compounds have better activity against Gram-negative bacteria than Gram-positive bacteria.According to the structure and antibacterial activity data of 3-aryl substituted and 3-alkyl substituted tetronic acids, we found that modifing the 3-tetronic acid by benzene and naphthalene ring improved their antibacterial activity; The addition of the halogen atoms in 3-benzene ring has better antimicrobial activity, particularly with fluorine. These results suggested us to add hydrophobic fluorine large groups at 3-position acid to improve their antibactierial activity.