Design,Synthesis,Structure-Antifungal Activity Relationship Of Novel Amides Containing Oxazoline And Analogues

Phenyloxazolines play an important role in the development of new pesticides and in organic synthesis.Previous works demonstrated the multifunctional potentials of 2-(2-oxazolinyl)aniline,which can be used as a directing group for direct C-H functionalization in organic synthesis and can also be used as a pharmacophore for the design of bioactive molecules as pesticide candidates.Novel antifungal nicotinamides aniline were obtained with 2-(2-oxazolyl)as an innate directing group,through the inexpensive copper-catalyzed C-H etherification.At the same time,novel antifungal amides containing 2-phenyloxazoline and analogues were designed and synthesized.The main results obtained are as follows:1.para-etherification of nicotinamides with commercially available phenols were achieved by Cu-catalyzed regioselective etherification with 2-(2-oxazolyl)-aniline as a directing group and intrinsic pharmacophore.31 nicotinamides were synthesized and the structure were confirmed by 1HNMR,13CNMR and MASS.Some desired compounds were also elucidated unambiguously by X-ray crystallographic diffraction.Using(R)-LE001 as a positive control,the target compounds were tested against Fusarium graminearum,Sclerotinia sclerotiorum,Rhizoctonia solani,Pyricularia oryzae,Botrytis cinerea,and Phytophthora capsici at the concentration of 10 mg/L.The antifungal activity assay showed that these compounds have a good inhibitory effect against Sclerotinia sclerotiorum,Rhizoctonia solani and Botrytis cinerea.Four nicotinamides,including A8,A12,A15 and A18,were protruded as antifungal candidates against Botrytis cinerea,with the EC50 value of 4.423 mg/L,4.625 mg/L,4.240 mg/L and 4.863 mg/L,respectively.Structure-antifungal activity showed that the substituents on the oxazoline ring is necessary for the improvement of the antifungal activity,and the substituents with 1-3 carbons showed advantages over the sterically bulky groups including phenyl and benzyl subunits.The substituent of the R configuration is better than the S-enantiomer in most cases.Molecular docking simulation was carried out for the antifungal candidates A7,A10 and A15,to explore the antifungal mechanism of the synthesized novel nicotinamide compounds.With 2-(2-oxazolyl)aniline as a directing group for the copper mediated C-H direct alkoxylation of nicotinamides was conducted.Optimization of reaction parameters was conducted,and N-ortho C-H ehtherification was realized with the aliphatic alcohol as a media,in presence of stoichiometric sodium carbonate and copper acetate as a base and the active metal species,respectively.A total of 23 alkoxylated nicotinamides were synthesized and confirmed by 1H NMR,13C NMR and MASS.The methoxylated product was also elucidated unambiguously by X-ray crystallographic diffraction.This reaction can introduce the alkoxyl groups to nicotinamide directly,which step-economy,high regioselectivity,high yield and easy operation.The bioassay showed that this kind of nicotinamides didn't improve antifungal activity obviously,compared to aryl ether counterparts.The methodology laid a solid foundation for the efficient preparation of novel nicotinic acid and nicotinamides and related pharmaceuticals.3.Based on Oxathiapiprolin and Pydiflumetofen,32 antifungal amides of 2-phenyloxazoline carboxylic acid and its bioisostere were designed and synthesized.All the products were confirmed by 1HNMR,13CNMR and MASS.The bioassay assay showed that these compounds have a good inhibitory effect against Sclerotinia sclerotiorum,Rhizoctonia solani and Botrytis cinerea.Compound D15,showed obvious inhibitory effect against Rhizoctonia solani and Botrytis cinerea,with the inhibitory rate of 86.4%and 88.6%respectively at 50 mg/L,which were better than that of the positive control Pydiflumetofen.Highly active compound D15 can be used as antifungal candidate.The structure-antifungal activity relationship confirmed the importance of bioisosteres in the discovery of new precursors,in which 2-Phenylthiazolinamides were selected as novel fungicide leads for further structural optimization.This lays a foundation for further structural optimization and discovery of new antifungal candidates.Based on 2-phenyloxazoline,three types of amides,including 85 compounds,were designed and synthesized.The structure-antifungal activity relationship was studied,which protrudes six antifungal candidates and the discovery of new C-H etherification.This will provide a new oriention for the structural optimization of amides containing phenyloxazoline for the rapid discovery of new antifungal candidates.