Synthesis Of 1,4-disubstituted 1,2,3-triazoles And Evaluation Of Their Quorum Sensing Inhibition

In the struggle against bacterial infectious diseases,antibiotic represent the most effective class of medication at our disposal.However,the increase of multidrug-resistant(MDR)strains,especially NDM-1 resistant strains,is now a worldwide concern and represents a serious public health issue.It is more urgent to find novel target antibacterial agents for researchers.Quorum sensing(QS)is a cell communication mechanism involving the generation,release and detection of small signaling molecules which can activate specific receptors associated with transcription signals that are responsible for controlling a variety of different biochemical processes.QS can effectively regulate some important phenotypes including the bioluminescence,virulence expression and formation of biofilm,which most of them are relevant to antibiotics resistance.In recent years,much more bacterial strains showed resistance to antibiotics,and it is urgent to find an effective solution.Thymidine derivatives are more widely used in the world of organic heterocyclic compounds;in particular,the amide structure of the pyrimidine ring has a potential quorum sensing inhibitory effect.They are concerned by people because they exhibit good biological and pharmaceutical activity etc.Therefore,the study of the synthetic heterocyclic compounds containing thymidine,isoxazole and 1,2,3-triazole has always been a search realm with vitality in the organic chemistry and medical chemistry.The structural features and physiochemical properties of their fragment are of great interest in drug design and discovery.In this work,we combined 1,2,3-trizole and isoxazole into thymidine derivative structure get novel target molecules,further evaluated their quorum sensing to Gram negative bacteria.Firstly,we synthesized series of 1,2,3-triazole compounds from 3-substituted phenyl isoxazolyl-5-ether alkynes and substituted thymidine azide by ultrasonic-assisted.Thus,Seven 5-hydroxy methyl thymidine-1,2,3-triazole compounds were obtained with 87? 96% yields.In a word,series of derivatives weresynthesized with short reaction time,less by-product and the much more friendly reaction condition.Besides,we characterized the compounds and analyzed by infrared spectroscopy FT-IR,1H and 13 C NMR and HRMS.The structures of the synthesized compounds were confirmed.Secondly,inhibitory activities against gram negative bacteria quorum sensing of the compounds were evaluated with chromobacterium violaceum CV026,which C10-HSL was a positive control.The compounds 8a,8c and 8f have good inhibitory activities against CV026 quorum sensing,which had no effects on bacteria growth.Finally,we were evaluated the quorum sensing inhibitory activity against Pseudomonas aeruginosa PAO1 of the synthesized compounds.The compounds 8a,8c and 8f displayed good activities against biofilm and pyocyanin.This indicated that novel 5-hydroxy methyl thymidine-1,2,3-triazole derivatives could be as candidates for as novel antibacterial agents.In summary,a series of 5-hydroxy methyl thymidine-1,2,3-triazole derivatives were synthesized by ultrasonic radiation technologies.The synthesized compounds displayed inhibitory activities against quorum sensing of Gram-negative bacteria and showed great application in medicine in future.