摘要/Abstract

基于在咖啡因8-位引入哌嗪活性基团的策略, 以8-氯茶碱和取代哌嗪为原料, 利用N-甲基化、亲核取代、(保护)脱保护等多步反应, 合成了16个新型含取代哌嗪的咖啡因衍生物Ia~Ip, 通过熔点、¹H NMR、¹³C NMR和HRMS对新化合物进行了结构确认和表征, 获得了8-(4-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-甲酰基)哌嗪-1-基)-1,3,7-三甲基-3,7-二氢-1H-嘌呤-2,6-二酮(Ip)的单晶结构. 生物活性测试结果表明, 目标化合物大多对小菜蛾(Plutella xylostella L.)和东方粘虫(Mythimna separata Walker)表现出显著的杀虫活性, 尤其针对小菜蛾, 部分化合物活性优于咖啡因, 其中8-(4-(4-氟苯基)哌嗪-1-基)-1,3,7-三甲基-3,7-二氢-1H-嘌呤-2,6-二酮(Ie)和1,3,7-三甲基-8-(4-(4-硝基苯甲酰基)哌嗪-1-基)-3,7-二氢-1H-嘌呤-2,6-二酮(In)在100 mg•L^–1分别具有60%和53%的致死率. 此外, 部分化合物在50 mg•L^–1测试浓度下对苹果轮纹病菌(Physalospora piricola)、小麦纹枯病菌(Rhizoctonia cerealis)和油菜菌核病菌(Sclerotinia sclerotiorum)等具有50%以上的抑制活性. 研究结果可为基于黄嘌呤类天然产物结构的新型农药分子设计提供重要参考.
关键词: 黄嘌呤, 咖啡因, 哌嗪, 合成, 杀虫活性, 抑菌活性
Based on a strategy of introducing the “piperazine” bioactive group into 8-position of caffeine, sixteen novel caffeine derivatives containing substituted-piperazine moiety (Ia~Ip) have been synthesized using 8-chlorotheophylline and substituted-piperazine as materials, via multi step reactions of N-methylation, nucleophilic substitution, (protection)deprotection, etc. The structures of the title compounds were confirmed and characterized by melting point, ¹H NMR, ¹³C NMR, and HRMS. The single-crystal structure of 8-(4-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carbonyl)piperazin- 1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Ip) was obtained. The bioassay results showed that most of the title compounds possess good insecticidal activities against Plutella xylostella L. and Mythimna separata Walker. In particular, some of the compounds exhibited better larvicidal effect towards Plutella xylostella L. than that of control caffeine, among which 8-(4-(4-fluorophenyl)piperazin-1-yl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (Ie) and 1,3,7-trimethyl-8-(4-(4- nitrobenzoyl)piperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione (In) at a test concentration of 100 mg•L^–1 held lethality rate of 60% and 53%, respectively. In addition, partial compounds at 50 mg•L^–1 concentration possessed >50% fungicidal activities against Physalospora piricola, Rhizoctonia cerealis, Sclerotinia sclerotiorum, etc. The research results in this paper provide useful reference for further design of novel agrochemicals based on the natural product structure of xanthine.
Key words: xanthine, caffeine, piperazine, synthesis, insecticidal activity, fungicidal activity


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