Synthesis And Herbicidal Activity Of Strobilurin Analogues Containing A Phenylpyridine Moiety

Strobilurin A is a natural antibiotic found in mushrooms.It exhibits a broad spectrum of bactericidal activity in vitro or in greenhouse conditions.However,it is not suitable for use as an agricultural fungicide with the characteristics of poor light stability and volatilization.In the 1980s,using strobilurin A as the lead compound,two new fungicides Azoxystrobin and Kresoxim-methyl were created respectively with high activity,broad spectrum and safety,which set off a research upsurge of strobilurin fungicides.This kind of fungicide has developed rapidly because of its unique mechanism,high activity,broad bactericidal spectrum,low toxicity and environmental friendliness.So far,more than ten strobilurin fungicides have been commercialized,and they have become one of the largest agricultural fungicide types.Strobilurin acaricide has also been marketed.However,strobilurin herbicide has not yet been developed successfully.Target of strobilurin compounds is the cytochrome bc1 complex,which is also acting an important role in the respiratory system and photosynthetic system in plants.Therefore,it is promising to create a novel type of strobilurin herbicide through structural optimizing of the strobilurin compounds.The herbicidal derivatives of pyridinylphenoxymethylenephenyl methoxyiminoacetic acid were firstly discovered by our group,which have the active group similar to that of the strobilurin compounds.In this paper,phenylpyridine structure was introduced into the active structure of Kresoxim-methyl,and the structural modification of lead compounds was carried out systematically.Four series of Kresoxim-methyl derivatives were synthesized,including seventy three 2-(substituted pyridylphenoxymethyl)phenyl oxime ether acetate compounds,tweenty five 2-(substituted pyridylphenoxymethyl)phenyl methoxy acrylate compounds,seventy two 2-(4-pyridyl substituted phenoxymethyl)phenyl oxime ether acetate compounds,and fourty bridge-modified 2-(substituted pyridyl)phenyl bridged phenyl oxime ether acetate compounds.The structures of all the synthesized Kresoxim-methyl derivatives were confirmed by NMR and HRMS.And the absolute configuration of compound I-36 was obtained by X-ray single crystal diffraction.Herbicidal activities assay in greenhouse tests indicate that compounds I-35 and I-36 showed about 100%inhibition against Eclipta prostrata,Abutilon theophrasti,Amaranthus retroflexus at 37.5 g a.i./ha,which was better than mesotrione.The herbicidal activities of other structural modified compounds were reduced to varying degrees.The structure-activity relationship of these compounds was revealed by the optimization of lead structure and the result of herbicidal activity.Herbicidal activities of Kresoxim-methyl derivatives with substituents at position 3 and 5 of pyridine ring are better than that of Kresoxim-methyl derivatives with substituents at position 4 and 6 of pyridine ring.Kresoxim-methyl derivatives with monosubstituted pyridine ring have poor herbicidal activities.Furthermore,herbicidal activities of compounds containing oxime ether acetate active structure are better than that of compounds containing methoxyacrylate active structure.Herbicidal activities of these compounds without group modification on the phenyl ring linked to pyridine ring was excellent.Kresoxim-methyl derivatives maintain marvellous herbicidal activities when oxygen atoms in the bridge chain are not substituted by sulfur atoms,nitrogen atoms,thionyl groups and sulfonyl groups.Herbicidal activities of these compounds are reduced by increasing carbon chains.Meanwhile,the importance of pyridine ring in maintaining herbicidal activity of Kresoxim-methyl derivatives was also proved.Compound I-35 and I-36 with super-high herbicidal activity were successfully obtained through the study of structure-activity relationship and the structural optimization of strobilurin herbicide candidates.And then,the bioactivities of compound I-35 and I-36 were evaluated systematically,including general screening test,primary screening test,crop safety test,selectivity test,herbicidal spectrum test,suitable period test,field efficacy test and toxicity test,etc.The results showed that the inhibition rates of compound I-35 and I-36 against broadleaf weeds such as Abutilon theophrasti,Amaranthus retroflexus and Chenopodium serotinum were close to 100%at 15 g a.i./ha.They are safe to wheat and have good selectivity between wheat and Chenopodium serotinum with selectivity coefficients of 88.93 and 57.15,respectively.Moreover,compound I-35 and I-36 have broad herbicidal spectrum.The results of field efficacy test showed that I-35 had better control effect on broadleaf weeds in wheat field at 100-200 g a.i./ha,which was similar to that of control agent 10%tribenuron-methyl wettable powder at 25 g/ha and the control effect of I-36 was 88.6%-92.8%under 100-200 g a.i./ha,which was significantly higher than or equivalent to that of control agent 10%tribenuron-methyl wettable powder at 50 g/ha.At the same time,compound I-36 has a LD50 value of more than 5000 mg/kg bw in rats,which belongs to the level of micro-toxicity.Ecotoxicity test shows that compound I-36 is safe for birds and bees.In conclusion,a series of strobilurin analogues containing phenylpyridine synthesized in this paper have shown good herbicidal activities and safety.Especially,I-35 and I-36 could be used as candidate herbicides for in-depth research and development,laying a good foundation for the creation of novel strobilurin herbicides with novel mechanisms of action.