【摘要】 利用活性拼接的原理,以杨梅苷为原料,将1,2,4-三唑并[3,4-b]-1,3,4-噻二唑引入到杨梅素结构中,合成了一系列含三唑并噻二唑的杨梅素衍生物,通过¹H NMR、¹³C NMR和高分辨质谱（HRMS）进行了结构表征,并通过X单晶衍射实验确认了3-（3-（（3-乙基-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫代）丙氧基）-5,7-二甲氧基-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A5）的结构.生物活性测试结果表明:浓度为100μg/m L时,3-（3-（（3-（4-（叔丁基）苯基）-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫基）丙氧基）-5,7-二甲氧基-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A15）对柑桔溃疡病菌（Xac）的抑制率为63.3%,优于对照药噻菌铜（57.3%）;部分化合物对烟草花叶病毒（TMV）表现出较好的抑制活性.其中,治疗活性方面,化合物A5,5,7-二甲氧基-3-（4-（（3-（甲氧基甲基）-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫代）丁氧基）-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A8）,5,7-二甲氧基-3-（3-（（3-苯基-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫代）丙氧基）-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A9）,5,7-二甲氧基-3-（4-（（3-（对甲苯基）-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫代）丁氧基）-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A12）的EC₅₀值分别为88.3,139.1,109.9,160.1μg/mL,优于对照药宁南霉素（227.2μg/mL）.保护活性方面,5,7-二甲氧基-3-（4-（（3-苯基-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫代）丁氧基）-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A10）,5,7-二甲氧基-3-（4-（（3-（4-甲氧基苯基）-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫基）丁氧基）-2-（3,4,5-三甲氧基苯）-4H-色酮-4-酮（A14）,3-（3-（（3-（4-（叔丁基）苯基）-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫基）丙氧基）-5,7-二甲氧基-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A15）,3-（4-（（3-（4-叔丁基）苯基）-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫基）丁氧基)-5,7-二甲氧基-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A16）,3-（4-（（3-（4-氯苯基）-[1,2,4]三唑[3,4-b][1,3,4]噻二唑-6-基）硫基）丁氧基）-5,7-二甲氧基-2-（3,4,5-三甲氧基苯基）-4H-色酮-4-酮（A18）的EC₅₀值分别为103.1,107.4,86.3,79.2,111.5μg/m L,优于对照药宁南霉素（179.2μg/mL）.微量热涌动实验表明,化合物A12和A16与烟草花叶病毒外壳蛋白（TMV-CP）具有较强的亲和力,分子对接实验表明,化合物A16与TMV-CP具有较强的相互作用.更多还原

【Abstract】 A series of myricetin derivatives containing 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole moiety were designed and synthesized using myricetin as the starting material through active splicing strategy.All target compounds were characterized by ¹H NMR,¹³C NMR and high-resolution mass spectra （HRMS）.Single crystal X-ray diffraction experiments were carried out with 3-（3-（（3-ethyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）propoxy）-5,7-dimethoxy-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A5）.When the concentration was 100μg/mL,the inhibition rate of 3-（3-（（3-（4-（tert-butyl）phenyl）-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）propoxy）-5,7-dimethoxy-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A15） against Xanthomonas axonopodis pv.citri （Xac） was 63.3%,which was better than that of the control drug thiophanate-copper（57.3%）.Biological activity test results that these compounds showed good inhibitory activity against tobacco mosaic virus（TMV）.Among them,in terms of therapeutic activity,the EC₅₀ values of compounds A5,5,7-dimethoxy-3-（4-（（3-（methoxymethyl）-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）butoxy）-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A8）,5,7-dimethoxy-3-（3-（（3-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）propoxy）-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A9）,and 5,7-dimethoxy-3-（4-（（3-（p-tolyl）-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）butoxy）-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A12） were 88.3,139.1,109.9,160.1μg/mL,respectively,which were better than the control drug ningnanmycin （227.2μg/mL）.In terms of protective activity,the EC₅₀ values of compounds 5,7-dimethoxy-3-（4-（（3-phenyl-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）butoxy）-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A10）,5,7-dimethoxy-3-（4-（（3-（4-methoxyphenyl）-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）butoxy）-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A14）,A15,3-（4-（（3-（4-（tert-butyl）phenyl）-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）butoxy）-5,7-dimethoxy-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A16）,and 3-（4-（（3-（4-chlorophenyl）-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl）thio）butoxy）-5,7-dimethoxy-2-（3,4,5-trimethoxyphenyl）-4H-chromen-4-one （A18） were 103.1,107.4,86.3,79.2,111.5μg/mL,respectively,which were better than the control drug ningnanmycin （179.2μg/m L）.Microscale thermophoresis（MST） indicated that compounds A12 and A16 have strong binding force to tobacco mosaic virus coat protein （TMV-CP）.Molecular docking experiments showed that compound A16 has a strong interaction with TMV-CP.更多还原