Design,Synthesis And Biological Activities Of Novel Oomycetes Fungicide Oxathiapiprolin Analogues

Oxathiapiprolin is the first new piperidyl thiazole isazolines oomycete fungicide developed by DuPont,which has both protective and curative activity.The compound has a new structural framework,consisting of five structural units:pyrazole-piperidine-thiazole-isoxazoline-benzene ring.Compared with other commercial fungicides,oxathiapiprolin has a novel action site and a unique action mechanism against oomycelium pathogens,which can achieve bactericidal effect by inhibiting Oxysterol-Binding Protein(OSBP).Oxathiapiprolin has very favorable toxicological and environmental characteristics,with low dosage,and higher safety for users,agricultural producers and the environment.When the dosage of oxathiapiprolin was as low as 12～30 g ai/ha,the effective period on potato late blight could reach 7-10 days.The minimum control concentration for cucumber downy mildew and pepper root rot was 12～30 g ai/ha,which was 1/100～1/5 of common fungicides.In addition to the significant inhibitory effect on oomycetes,this fungicide has been widely used in fruits,vegetables,tobacco,sunflower and other cash crops,and has received extensive research and attention.In this thesis,oxathiapiprolin was taken as the lead compound,Through literature research and previous research work of the research group,combined with structure-activity relationship analysis,bioelectron arrangement,active substructure splicing principle and other drug molecular design strategies,We designed and synthesized two series of a total of 62 new oxathiapiprolin analogues,respectively is contain propylene cyanide structure series I and contain fused heterocycle segments series Ⅱ(as shown in the following figure).The most important structural feature was that the thiazole ring and isoxazoline fragment were basically in the same plane.Therefore,in this thesis,the coplanar double bond was introduced to form the propylene cyanide structure instead of the isoxazoline ring,making the new compound consistent in three-dimensional configuration.On the basis of literature research,we found that propylene cyanogen structure has been widely used in the field of drug molecules,according to our previous research work,again through the structure-activity relationship analysis of synthetic compounds,combined with bioelectron arrangement,active substructure splicing principle and other drug molecular design strategies,We designed and synthesized two series of a total of 62 new oxathiapiprolin analogues,respectively is series I which containing propylene cyanide structure and series II which containing fused heterocycle segments(as shown in the following figure).Further study on the physicochemical properties,structural characterization and bactericidal activity of the above target compounds showed that three of the synthesized compounds had good bactericidal activity and entered the furtherscreening stage.In this paper,the bactericidal activity and structure-activity relationship of all the compounds were analyzed and summarized in detail,which provided a reference for future research work.The specific research contents are as follows:1.The diseases caused by oomycetes,the types and mechanisms of action of fungicides were introduced,and the discovery,optimization process,research status of the lead compounds of oxathiapiprolin,as well as the structure and function of targets were systematically introduced.2.The bactericidal activity of the synthetic oxathiapiprolin analogues was tested for cucumber downy mildew in laboratory potted plants.The results showed that the control effect of the target compounds Ⅰ-13,Ⅰ-24,Ⅰ-27,Ⅰ-28,Ⅰ-29,Ⅰ-32,Ⅱ-11,Ⅱ-12 and Ⅱ-28 could reach more than 70%control efficiency under the low concentration of 1.25 mg/L at the initial screening.Among them,the target compounds Ⅰ-29,Ⅱ-11 and Ⅱ-12 entered the further screening stage,Compared with the control agent oxathiapiprolin,the compound had almost no control effect on cucumber downy mildew and potato late blight.3.The structure-activity relationships of the target compounds at the in vivo level were analyzed and summarized,which provided guidance for the subsequent structural modification,and the development of more efficient oxathiapiprolin analogues for inhibition of oomycetes.