Design,Synthesis,Fungicidal Activity And SAR Of Mandelic Amides Containing Chiral Oxazolines

Pesticides play an important role in modem agriculture,ensuring high quality of food supply.On the other hand,the accompanied pesticide residues,negative impact on the environment,and resistance are becoming increasingly serious.New pesticides with high efficiency,low toxicity,resistance,economy,and environment-friendly will be one of the important approaches.Discovery of chiral pesticides is one of the most effective approaches catering to the requirements,by interacting with the potent protein target specifically,with reduced or non-influence on other organisms and the environment.Natural products can serve as good scaffolds or precursors for the discovery and creation of new pesticides.Inspired by the established the succinate dehydrogenase inhibitors(SDHIs)model,Our continuing efforts to the discovery of chiral antifungal amides were marched to the optimization of the polar part with 2-(2-oxazolinyl)aniline as a pre-validated pharmacophore.Our campaign was engaged in the introduction of mandelic acids and analogues for novel amides of the 2-(2-oxazolinyl)aniline.The following results were obtained as follows:(1)45 new mandelic amides with 2-(2-oxazolinyl)aniline as a pre-validated pharmacophore were designed and synthesized based on the mandelic agrochemicals and bioactive oxazolines.Structural elucidation of all the targets compounds were carried ouy by Electrospray Ionization Mass Spectrometer(ESI-Mass),1H-Nuclear Magnetie Resonance(1H-NMR)Spectroscopy,13C-Nuclear Magnetic Resonance(13C-NMR)Spectroscopy and X-ray single-crystal diffraction were also included in the structural characterization.(2)The in vitro antifungal activity of the target compounds was determined by the mycelial growth method,against Botrytis cinerea,Rhizoctonia solani,Sclerotinia sclerotiorum,Phytophthora capsici and Pyricularia oryzae,with boscalide as a positive control.The results showed that the target compounds had moderate to good antifungal activities.Compounds A15,A22,A23 demonstrated good antifungal effect against Rhizoctonia solani(with ECso of2.98+0.21 mg/L),Sclerotinia sclerotiorum(with EC50 of 3.95±0.51 mg/L)and Botrytis cinerea(2.95±0.37 mg/L),respectively.Compound A7 possessed prominent inhibition against Botrytis cinerea and Rhizoctonia solani,with EC50 values of against were as 3.83±0.12 and 5.76±0.17 mg/L,respectively.Significant chiral effect of mandelic acid subunits on antifungal activities was observed,and both bulkiness and chirality of substituents on oxazoline rings showed impacts on bioactivity.The isomers from the mandelic acids and oxazoline with the same configuration showed advantages over their enantiomers.The target compounds with R-Ethyl group decorated on the oxazoline ring showed wide and good antifungal effects.(3)The preventative efficacy of compound A7 against Botrytis cinerea was demonstrated by in vivo biotest and up to 93.9%protective effect was achieved at the concentration of 50 mg/L,which was superior to the positive control boscalid(90.6%).Compound A22 showed good preventative efficacy(72.7%)against Sclerotinia sclerotiorum at 200 mg/L.Compound A23 can significantly inhibit spore germination of Pyricularia oryzae,with the inhibitory rate of 92.4%at 10 mg/L.Molecular docking studies using SYBYL-X2.0 software revealed that the isomers of A7 and compound A23 have different binding modes with potential target proteins(PDB:2FBW)3 which provide preliminary explanations for the differences in bioactivities.In summary,45 novel mandelic amides containing chiral oxazoline were designed,prepared and explored for the discovery of agrochemical candidates.Compound A7 emerged as a promising antifungal ingredient against Botrytis cinerea,showing advantages over the positive control boscalid in both efficacy and synthetic accessibility.Surflex-Docking was also conducted for this kind of chiral amides for explanation of biological difference and design of new antifungal ingredients.This work will give more insights into the discovery of chiral alkaloid fungicides based on oxazolines targeting SDH in the respiratory chain.