Synthesis And Antibacterial Activity Of Pyridinyl Isooxazoline And Oxazolidinone Heterocyclic Derivatives

Bacterial infections cause a variety of veterinary diseases,and the emergence and development of drug resistance causes significant economic losses to the breeding industry.Oxazolidinones are a class of chemosynthetic antibacterial drugs with brand new c hemical structure and mechanism of action,which has been widely modified because of its new chemical structure and unique antibacterial mechanism.So far,in a large number of oxazolidinone derivatives with novel structure,the modification of morpholine and C-5 side chain has produced many effective products,while the modification of benzene is rarely heard.In order to explore the influence of different s tructures and substituents on the effect of oxazolidinone antibacterial drugs,in this experiment,using oxazolidinone antibacterial drugs as lead compounds,through the replacement of phenyl ring by pyridine ring,a series of pyridine isooxazoline and oxazolidinone heterocyclic derivatives were designed and synthesized,and their antibacterial activities were tested.Taking oxazolidinone 1-27 as the lead compound,we modified its structure,introduced pyridinyl into the B ring,and designed and synthesized 12 pyridinyl isooxazoline compounds（2-9a～l）by changing the C-5 side chain.After its structure was confirmed by ¹H-NMR,¹³C-NMR and MS spectra,the inhibitory effect of 2-9a～l on the growth of multiple strains was studied by microbroth dilution method.The results showed that compounds 2-9e and 2-9l had better antibacterial effect.According to the above screening results,linezolid was used as the lead compound,and its structure was modified to introduce pyridinyl into the B ring.By changing the C-5 side chain and morpholine ring,17 pyridinyl oxazolidinone ester compounds（2-30a～i and 2-31a～h）were designed and synthesized.After its structure was confirmed by¹H-NMR,¹³C-NMR and MS spectra,the inhibitory effects of target compounds 2-30a～i and 2-31a～h on the growth of multiple strains were studied by microbroth dilution method.The results showed that compounds 2-31a and 2-31g had better antibacterial effects.Due to the poor stability of these compounds,further structural optimization was carried out.The N atom was introduced into the C-5 side chain,and 30 pyridinyl oxazolidinone compounds（2-32a～l,2-33a～l and 2-34a～f）were designed by changing the morpholine ring,C-5 side chain and fluorine atoms on the pyridine ring.The ring closing reaction conditions were explored and optimized during the synthesis process.The final yield of the ring closing product was 78.6%,and the yield of the ring closing reaction was increas ed by 48.6%.After its structure was confirmed by ¹H-NMR,¹³C-NMR and MS spectra,the inhibitory effects of target compounds2-32a～l,2-33a～l and 2-34a～f on the growth of multiple strains were studied by microbroth dilution method.The results showed that compound 2-34d had better antibacterial effect,and the structure-activity relationships of heterocyclic derivatives of pyridine isooxazoline and oxazolidinone were analyzed and summarized based on the screening results of the above compounds.The effects of compound 2-34b～f on the morphology of Streptococcus pneumoniae and Staphylococcus aureus were observed by scanning electron microscopy.The results sh owed that the compound could induce adhesion dissolution and cell wall damage at the subinhibitory concentration.The bacterial growth curve before and after administration of the compounds 2-34d was plotted by absorbance measurement.The results showed th at these compounds matched the shape of the target sites,which helped to reduce binding energy and improve antibacterial effect.On the basis of these results,the effects of compounds 2-34a～f on biofilm formation were determined by crystal violet method.The results showed that these compounds had certain anti-biofilm activity,and the minimum biofilm formation inhibition concentration of the optimal compound was 0.5μg/m L,4 times that of linezolid.Compound 2-34d,which is representative in the inhibition activity of biofilm formation,was selected.The gradient ascending induction resistance method was used to determine its anti-resistance activity.The results showed that compound 2-34d had better anti-resistance effect than linezolid,and induced obvious drug-resistant flora within 15 days of administration.In general,on the basis of summarizing the structure-activity relationship of oxazolidinone compounds,this study designed and synthesized a series of pyridine isooxazoline and oxazolidinone heterocyclic derivatives,and analyzed and summarized their structure-activity relationship.These compounds have long-lasting,stable and excellent antibacterial effects,and have the value and potential for further transformation.These results provide experi mental basis and theoretical basis for the development of novel oxazolidinone antibacterial drugs.