Design,Synthesis,Fungicidal Activity And Sar Of Chiral Oxazolines Alkaloids Based On Spoxazomicin C

Natural active substances can be used directly or as models for the discovery of new pesticides,the natural products of plant source or microbial source is one of the important approach.Natural products containing oxazoline have important biological activity and play an important role in medicinal chemistry,pesticide chemistry and organic synthesis,spoxazomicin C was isolated from the secondary metabolite of Streptosporangium oxazolinicum K07-0460T for the first time in 2011,which has a good antipollosome activity and antibactericidal activity.It has a simple structure and showed chiral difference in bioactivity,which can be modified and sceitable for structure optimization.Herein,a series of chiral oxazoline compounds were designed and synthesized with spoxazomicin C as the lead compound.The results were as follows:(1)Based on the natural product spoxazomicin C and the commercial fungicide boscalid,28 nicotinamide compounds(3aa-3fd)containing chiral oxazoline were designed,synthesized charactericed by the determination of physical properties,1H-NMR,13C-NMR and ESI-MS.The in vitro antifungal activity of the target compound against Rhizoctonia solani,Botrytis cinerea and Sclerotinia sclerotiorum was determined by the inhibition of mycelial growth rate with boscalid as positive control.The results showed that the target compound showed good antifungal activity,and the compound 3ad was the most prominent,of which the EC50 against Rhizoctonia solani,Botrytis cinerea and Sclerotinia sclerotiorum was as low as 4.99,3.14 and 11.29 mg/L,showing comparefine bioactivity to that of boscalid.The antifungal activity of these compounds exhibits a significant chiral difference,the R stereoisomer is significantly higher than that of its enantiomers.(2)With 3ad as a model,optimization was focused on the modification of car boxylic acid fragment and 2-phenyl oxazoline fragment to obtain novel chiral oxazol ine aminde with more promising antifungal activities.The physical constants,structu ral identification,and in vitro biological activity were determined through the aforent ioned methods.The results showed that the activity of the carboline-3-carboxylic aci d amide compound 5kd was much better than that of the positive control boscalid,with EC50 of 3.5.mg/L against Gaeumannomyces gramini.Compound 3ai showed gr eat antifungal activity,with the EC50 values of 0.58,0.42,2.10,4.01,8.2,3.30 mg/L against Rhizoctonia solani,Botrytis cinerea,Sclerotinia sclerotiorum,A.solanisora uer,Fusarium moniliforme,Gaeumannomyces gramini,respectively.(3)In vivo biotest and molecular docking of 3ai and 3ah were carried out to explore the potential for the discovery of noval peticides with boscalid as positive control.The results showed that the protective effect of compound 3ai on tomato gray mould,rape sclerotinia rot were 54.0%and 55.4%.Surflex-Docking results showed that compound boscalid,3ai and its enantiomer 3 ah were embedded well in the same protein groove established by extraction of carboxin from the original protein crystal(PDB code 2FBW).Interestingly,although our design of novel nicotinamides was based on the commercial boscalid,the embedded subunits were different.The substructurenicotinamide of boscalid is buried in the protein cavity,whilethis situation changed to oxazoline for both compounds 3ai and 3ah,casting the pyridyl ring out.Surflex-Docking results score of 3ah,3ai and boscalid were corresponding to their activity differences.The results of molecular docking provided a good explanation for the difference between compound activities,to a certain extent,also revealed that the design of synthetic targets may have a different mechanism of action with boscalid.Inconclusion,77 compounds were synthesized,in which 75 compounds were reported for the first time,the antifungal bioactivities SAR were completed,and the compounds with good activity were subjected to in vivo experiments and molecular docking experiments,which laid the foundation for the creation of new chiral fungicides containing oxazoline.