The Design, Synthesis And Anti-plant Virus Activity Of 3-substituted Phenyl-quinazolinone Sulfide Compounds Containing Dithioacetal Structure

As a class of natural alkaloids,quinazolinone has been widely used in medicine and pesticides because of its wide range of biological activities.At present,as a leading structure of natural sources,it has gradually become one of the hot spots of compoud derivation.In recent years,pesticide scientists have found that quinazolinone compounds have good antiviral activity,but the control effect is not satisfactory.In order to find the high-efficiency,low-toxicity,and environmental friendly antiviral drugs,this article takes the natural product quinazolinone as a lead compoud,and introduces a dithioacetal unit with antiviral activity via the principle of active substructure splicing.A series of 3-substituted phenyl-quinazolinone sulfide compounds containing ditioacetal moiety were designed and sythesised;and the heart-leaf tobacco and Nicotiana benthamiana were used as model plants to test the activity of the target compounds against tobacco mosaic virus,and systematically evaluated the in vitro and in vivo activity against tomato chlorotic virus;The work of this paper is summarized as follows:1.Based on the previous research on quinazolinone and dithioacetal compounds in our research group,we used quinazolinone as a lead compound,and introduced dithioacetal active groups with antiviral activity,tweenty eight novel 3-substituted phenyl-quinazolinone sulfide compounds containing dithioacetal structure were desighned and sytheised.All compounds were characterized by ¹H NMR,¹³C NMR,and HRMS.2.Using heart leaf tobacco as a model plant,the half-leaf spot method was used to test the inhibitory activity of the target compound against Tobacco mosaic virus?TMV?at 500?g/m L.The biological activity test result showed that:The majority of compounds showed good inhibitory activity on TMV,among which the curative activity of compounds D11,D15,D16,and D20 was 68.3%,70.9%,68.6%,and69.2%,which were better than the control agent ribavirin?50.3%?and Ningnanmycin?61.8%?.The protective activities of compounds D3 and D22 were 63.3%and 68.3%,respectively,which were equal to the control drug Ningnanmycin?65.1%?.The inactivating activity of Compounds D17,D20,and D27 was 88.7%,89.5%,and88.3%,which were equal to the control drug Ningnanmycin?90.5%?.3.The activities in vitro and in vivo of the target compounds against ToCV were systematically evaluated.We used ToCV CP as a potential drug target and tested the dissociation consistants of tweenty eight target compounds to ToCV CP by microthermophoresis?MST?.Most of the compounds showed good affinity,of which the affinity of compounds D8 and D16 bound to ToCV CP all reached micromolar levels,respectively 0.19 and 0.81?M.In order to further verify the activity in vitro,we used the ToCV-infected Nicotiana benthamiana as a model plant.After uniformly smearing 500?g/m L of the drug solution,the relative expression level of the ToCV CP gene in the Nicotiana benthamiana was tested by quantitative polymerase chain reaction?q PCR?.The test results showed that the compounds D8 and D16significantly reduced the relative expression level of ToCV CP gene in Nicotiana benthamiana.Compound D8 reduced the relative expression level of ToCV CP gene by 93.4%,which was slightly better than the control agent vanillin thioglycidyl ether?88.31%?and significantly better than the control agent Ningnanmycin?68.14%?.Compound D16 reduced the relative expression level of ToCV CP gene by 83.47%,which was significantly better than the control drug Ningnanmycin?68.14%?.The in vivo test results are consistent with the in vitro activity results.