Design, Synthesis And Biological Evaluation Of AI-2Bacteria Quorum Sensing Inhibitors

Quorum sensing (QS) is a communication procedure that predominates gene expression in response to cell density and fluctuations in the neighboring environment as a result of discerning molecules termed autoinducers (AIs). It has been embroiled that QS can govern bacterial behaviors such as the secretion of virulence factors, biofilm formation, bioluminescence production, conjugation, sporulation and swarming motility.Therefore, interfering with QS and discovering inhibitors of the bacterial could lead to a valuable beneficial anti-pathogenic strategy for the development of antimicrobial agents. It should be underlined that unlike conventional antibiotics, these quorum sensing inhibitors would not necessarily kill bacteria directly, but inhibit their virulence only. Hence, quorum sensing inhibitors are called as mild or soft antibiotics.Autoinducer2(AI-2), a QS signaling molecule brought up to be involved in interspecies communication, exists in both gram-negative and-positive bacteria. Therefore, novel molecules to interrupt AI-2quorum sensing are being recognized as next generation antimicrobial agents. Recently, most of the AI-2QSIs reported in the literature were designed according to the receptor LuxP. However, the procedure that the receptor LuxP binds to LuxQ to form LuxPQ complex generally causes a conformational change. More importantly, the receptor LuxPQ protein only exists in bacterial AI-2-type quorum sensing, and the corresponding protein as well as homologous family are not present in the mammalian body. Therefore, LuxPQ as a target for AI-2quorum sensing inhibitors is more accurate than LuxP, and LuxPQ inhibitors should be highly selective and specific.Based on two inhibitors AN-465/43369623and AH-262/34399019we discovered before, we employed the CHARMM program for molecular dynamics (MD) simulations to investigate the mode of action of lead compounds with the LuxPQ protein. Meanwhile, pharmacophore model were constructed using DS/Hiphop as well. Based on the structural information above, we designed and synthesized three series of triazole, furan and imidazole derivatives (about78compounds)In the biological evaluation, we chose the MM32strain of V. harveyi for screening the anti-quorum sensing effect of all compounds synthesized. Inhibition was measured by decreases in bioluminescence produced in V. harveyi. As a result, most of these molecules exhibit well inhibitory activities. It should be noted that molecules11h and11d were found to exhibit AI-2inhibition effect with IC50values in the single digit micromolar range (7.4±1.7μM and8.8±2.9μM respectively), compared with the IC50value of KM-03009(positive control) is8.9±1.7μM. In addition, several furan compounds were also evaluated for their bacterial growth inhibition, and most of them showed no significant growth inhibition except13a、11d、13k and13m. The structure-activity relationship for these compounds was discussed herein as well.