Design,Synthesis And Activity Study Of Fusarium Graminearum Myosin Ⅰ Inhibitor

The phenamacril（JS399-19）,is a novel cyanoacrylate fungicide discovered by the Jiangsu Branch of National Pesticide Research and Development South Center,which has high antibacterial activity against Fusarium（such as Fusarium graminearum,Fusarium asiaticum,Fusarium fujikuroi and Fusarium oxysporum）.Studies on comparative genome and genetic transformation have shown that myosin I is the key specific motor protein of Fusarium graminearum.Currently,the crystal structure of phenamacril and myosin I has been resolved.The recent studies have found that most of the Fusarium graminearum resistant population obtained are medium and high-level resistance under the conditions of indoor induced domestication of phenamacril.And it indicated that phenamacril has a higher risk of drug resistance.In order to develop a new myosin I inhibitor,this paper intends to use computer-aided drug design（CADD）strategy to design and synthesize a series of phenamacril analogues based on the composite crystal structure of phenamacril and myosin I.According to the binding mode of phenamacril with the amino acid residues Ser217 and Lys537 of myosin,and the different regions of the activity site of the binding protein（exposed region,connecting chain region and closed region）,three types of target compounds were designed.Representative compounds were selected for molecular docking simulation with target proteins,and 25 compounds（including amides,sulfonamides and cyanobacterium esters）were identified.The target compounds were obtained by a mild and economical synthesis method,and the structure of the compounds was confirmed by MS,IR,¹H NMR and ¹³C NMR.The in vivo activity of the compounds was preliminarily determined by the mycelial growth rate method,and the results showed that some of the compounds exhibited good mycelial growth inhibitory activity,among which compounds A1,A2,A6 and B1 showed equivalent in the tested pathogenic strains to phenamacril as a control.From the result of activity determination,it can be seen that the phenamacril derivatives modified on the benzene ring have a good antibacterial effect,and compounds such as amide/sulfonamide have no activity against the corresponding pathogens.It was confirmed that the effect of enhancement on amino acid residues in the exposed area may be improved activity of phenamacril derivatives.This study provides a reference for the application of computer-aided drug design in the development of new pesticides and lays a foundation for the further development of new myosin inhibitors.