分會(huì)

第五十七分會(huì)：農(nóng)業(yè)化學(xué)

摘要

天然黃嘌呤類生物堿如茶堿、咖啡堿等與人們的日常飲食密切相關(guān)，在農(nóng)藥化學(xué)領(lǐng)域已逐漸顯示出多樣的生物活性，通過黃嘌呤基本骨架引入各種農(nóng)藥活性基團(tuán)的策略設(shè)計(jì)合成新型農(nóng)藥先導(dǎo)化合物具有較大的研究潛力和一定應(yīng)用前景[1-3]。哌嗪衍生物不僅具有醫(yī)藥以及殺蟲、抑菌、除草活性，還可作為酮醇還原酸異構(gòu)酶（KARI）的抑制劑[4-7]。KARI在支鏈氨基酸的合成中發(fā)揮著重要作用，且由于KARI僅存在于微生物和植物體內(nèi)，以KARI為靶標(biāo)設(shè)計(jì)的農(nóng)藥分子具備對(duì)人和哺乳動(dòng)物安全等優(yōu)點(diǎn)?；谙蚣谆S嘌呤中引入哌嗪活性基團(tuán)的策略，以茶堿、8-氯茶堿和取代哌嗪等為原料，通過親核取代反應(yīng)、Mannich反應(yīng)合成了不同系列的新型7-或8-位含哌嗪基團(tuán)的黃嘌呤衍生物。生物活性測(cè)試結(jié)果表明，部分目標(biāo)化合物對(duì)小菜蛾和東方粘蟲均表現(xiàn)出一定的殺蟲活性，尤其針對(duì)小菜蛾，部分化合物在10 mg·L-1濃度下仍具有明顯的致死活性；部分化合物對(duì)蘋果輪紋病菌、油菜菌核病菌和小麥紋枯病菌具有70%以上的抑制率。部分化合物對(duì)KARI也展現(xiàn)出良好的抑制活性，值得作為新型KARI抑制劑進(jìn)行進(jìn)一步研究。通過分子前線軌道理論計(jì)算和高活性化合物與KARI酶結(jié)構(gòu)的分子對(duì)接，闡釋了化合物的活性基團(tuán)以及可能的作用方式。本研究結(jié)果對(duì)基于天然產(chǎn)物結(jié)構(gòu)的新型農(nóng)藥分子設(shè)計(jì)和開發(fā)具有一定的參考意義。 Natural xanthine alkaloids such as theophylline and caffeine are closely related to people's daily diet, and have gradually shown a variety of biological activities in the field of pesticide chemistry. The design and synthesis of novel pesticide lead compounds via the strategy of introducing various pesticidal active groups into the xanthine structural skeleton has great research potential and certain application prospects. Piperazine derivatives not only have pharmaceutical, insecticidal, fungicidal and herbicidal activities, but also are inhibitors of ketol-acid reductoisomerase (KARI) which is a key enzyme catalyzing the synthesis of branched-chain amino acids. As KARI only exists in microorganisms and plants, the designed pesticidal agents targeting KARI should possess the advantages such as safe for human and other mammals. Based on the strategy of introducing bioactive piperazine motif into the methylxanthine skeleton, various series of novel xanthine derivatives with piperazine group at 7-/8- position were synthesized via nucleophilic substitution reaction and Mannich reaction from starting materials of theophylline, 8-chlorotheophylline and substituted piperazines. The bioassay results showed that most of the target compounds exhibited certain insecticidal activities against Mythimna separata Walker and Plutella xylostella L.; especially towards the latter one, partial compounds still exhibited apparent larvicidal activities at a concentration of 10 mg·L-1. Some of the compounds showed > 70% inhibition rate against Physalospora piricola, Sclerotinia sclerotiorum and Rhizoctonia cerealis. Partial compounds also exhibited good inhibitory activities against KARI, and could serve as new KARI inhibitors for further investigation. Through molecular frontier orbital theoretical calculations and molecular docking of highly active compound with KARI enzyme structure, the active groups of the compound and possible mode of action were further elucidated. The results of this study are of reference value for the design and development of novel pesticidal agents based on the structure of natural products.

關(guān)鍵詞

黃嘌呤;哌嗪;殺蟲活性;殺菌活性;KARI酶

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