| Objective: Quorum sensing inhibitors(QSIs),which could interfere with the quorum sensing system but without causing resistance,represent an important breakthrough in the development of new antibacterial drugs.Recently,IQS,a newly discovered QS signaling molecule for Pseudomonas aeruginosa was studied for its novel mechanism in las system.However,due to the structure-activity relationship is not clear,no research related to the design and study of QSI using IQS as template has been reported so far.In order to develop novel compounds with high potenty new mechanism in antibiosis,a series of IQS derivatives were rational designed and synthesized.Evaluations of the anti-biofilm activity have also been completed.Methods:(1)Rational design: IQS was used as a template compound for structural expansion,two core pharmacophore elements were confirmed as aromatic ring and thiazole ring,based on which three group compounds were designed.(2)Synthesis: 33 derivatives were synthesized from thiazole-4-carboxylic acid through esterification and amidation.(3)Activities evaluation: MIC assay were established for all the compounds by the micro-broth dilution methodology,anti-biofilm activity were also tested via by crystal violet staining to assess the bacteriostatic abilities.Results:(1)In this paper,33 new compounds were synthesized,and all the structures of these compounds were confirmed by 1H-NMR,13C-NMR and MS.(2)Bioassay results: Amidation compounds showed potential antibiofilm activities against POPA.Results of anti-biofilm showed that 28 obtained a good inhibitory effect on bio-film formation.Conclusions: The structure-activity relationships of the IQS derivatives against the biofilm formation were summarized based on the biological activities of all compounds.New compound 28 showed a good inhibitory activity on biofilm formation,providing a better lead compound for further drug design and theory basis for the optimization of IQS derivatives. |
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