Design, Synthesis And Activity Evaluation Of Bacterial Quorum Sensing Inhibitors

In the growth process of bacteria, they can produce chemical signal moleculesand secret them into the surrounding environment. When the number of signalmolecules reaches to a certain threshold, the expression of related genes will beregulated to adapt to the environmental changes such as the biofilm formation,bioluminescent, et al. This phenomenon is called quorum sensing (QS). So far, QShas been discovered in more than50bacteria, including P.aeruginosa and E.coil.Inhibiting the quorum sensing system can restrain the expression of harmful genes.QS inhibitors make pathogens lose pathogenicity by blocking the expression ofharmful genes, they do not interfere with the normal physiological activity of bacteria,which is regarded as a new direction of the antimicrobial drugs’ development. Thepurpose of this paper is to synthesize a new type of bacterial quorum sensinginhibitors, which can be used for the treatment of diseases caused by resistantgram-negative bacteria. The AHL analogues which have the most effective study,inhibit QS system mediated with N-acylhomoserine lactones (AHLs) molecules. Thetarget of our project is to design QS inhibitors against the quorum sensing system ofAHLs signal molecules.In this paper, we researched QS inhibitors using C.violaceum as bacterial model.N-sulfonyl homoserine lactone derivatives have been designed by thestructure-activity relationship analysis. First of all, we reserved the S-type homoserinelactone nucleus, benzenesulfonyl was introduced between nucleus and amide group,which could improve hydrophobicity and had broad biological activity. In order toexplore the effect to QS inhibitory activity, a series of five-, six-memebered aromaticheterocyclics and phenethyl groups were connected after benzenesulfonyl side chain.Starting from the simple and available materials, through multistep reaction,33target compounds were synthesized. The structures of all the compounds wereidentified by methods of MS and1H-NMR. The biological activities of target compounds were evaluated through the violacein inhibition in Chromobacteriumviolaceum CV026.16compounds had antagonist effect and compound7-9showedthe best antagonist activity. Studies of structure-activity relationship showed thatN-acylhomoserine lactone compounds with a five-membered aromatic heterocyclicsubstituted in side chain showed better activity than those substituted by phenethylgroups on the same position. Five-membered aromatic compounds which connectedelectron withdrawing group had better inhibitory activity than those connectedelectron donating group. Further analysis of thiazolyl groups showed that orthosubstituted thiazolyl groups with electron withdrawing group were superior the paraand meta substituted thiazolyl groups. The inhibitory activity of compound7-9wasthe best, which could be used for further development.