Design,Synthesis And Antibacterial Activity Of PFK-158 And Its Derivatives

ObjectiveDrug resistance has become one of the biggest health threats to human health.It is reported that PFK-158 combined with polymyxin can enhance the antibacterial activity of polymyxin,but there is no report about PFK-158 used alone for antibacterial activity.Therefore,it is of great significance to study the antibacterial activity of PFK-158 and its derivatives for the development of novel antibacterial drugs against drug-resistant bacteria.MethodsA series of novel PFK-158 derivatives were designed and synthesized with PFK-158 as the lead compound,and the synthetic route of the target compounds was determined:compounds A were synthesized by Claisen-Schmidt condensation of substituted quinoline formaidehyde with acetylpyridine;Compounds B were also prepared by Claisen-Schmidt condensation of 7-trifluoromethylquinolin-2-yl-ethanone or 2-acetylnaphthalene with pyridine formaldehyde,respectively;Compounds C were obtained by the reaction of some compound A and B with methyl iodide.The antibacterial activity in vitro of the target compounds was determined by agar dilution method with levofloxacin as positive control.The combination of polymyxin and some target compounds was analyzed by chessboard assay.At the same time,its cytotoxicity was tested by sulfonyl rhodamine staining.ResultsPFK-158 and its 35 unreported derivatives were designed and synthesized.The chemical structures of the target compounds and intermediates were confirmed by HRMS,¹H NMR and ¹³C NMR.The results of pharmacological experiments showed that:（1）PFK-158 and its derivatives had no antibacterial activity against Gram negative bacteria.The MIC values of 11 compounds were between 1-4μg/m L.These target compounds had better antibacterial activity against MRSE,which were 2-8 fold than that of levofloxacin.Among them,the target compounds A1,A3,A14,A15 and B6 also had potent antibacterial activity against MSSA with MIC value of 1μg/m L,but inferior than levofloxacin.（2）The results of chessboard assay with polymyxin showed that the target compounds A11,A12,A13（PFK-158）and B6 had significant synergistic effect when combined with polymyxin,and the FICIs based on the combination of polymyxin were all lower than 0.5.The synergistic effects of target compounds A11,A12,B6 with polymyxin were similar to that of PFK-158.The MIC values of all E.coli resistant bacteria,whether they are mcr-1 positive or negative isolates,can be reduced to 2μg/m L.For E.cloacae D01,a mcr-1 negative isolate,the MIC values of these compounds could be reduced to 128 fold of the sensitive level.（3）The results of cytotoxicity test showed that the IC₅₀values of target compounds A1,A2,A3,A11 and A12 were higher than that of PFK-158,indicating that these five compounds have more development prospects.The preliminary structure-activity relationships showed that:（1）Quinoline ring was an essential group for antibacterial activity.The position of N atom could affect the antibacterial activity,N atom at m1 position of M ring was benefit for antibacterial activity.The trifluoromethyl group also contributed to the antibacterial effect,but its position was not important.（2）Pyridine ring was also an essential group for antibacterial activity.The position of N atom also affected the activity of target compounds.Compounds with N atom in the ortho position of theα,β-unsaturated carbonyl group were more active.（3）The target compounds containing oppositeα,β-unsaturated carbonyl with PFK-158 might change the original antibacterial activity.（4）Quaternization could reduce the the antibacterial activity of PFK-158derivatives.ConclusionsThe synthesis and antibacterial activity test of PFK-158 and its derivatives were studied.It was found that PFK-158 and its derivatives had potent antibacterial activity against Gram-positive bacteria.This provides a new development direction for the research of antibacterial drugs,and valuable clues for solving the problem of bacterial resistance.