利用簇合效应与类同法合成新农药活性化合物的研究
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摘要
农药是农业生产的重要保障物资,在国民经济发展中具有重要的作用。高效、低毒、环境友好是21世纪农药新品种发展的趋势。为了筛选与发现结构新颖的具有农药活性的化合物,本文利用簇合效应和类同合成两种新农药创制方法,设计合成了4个系列的化合物,并进行了生物活性评价。可分为以下两个部分:
第一部分:利用簇合效应原理合成双作用位点抑制剂
1、基于乙酰乳酸合成酶(acetohydroxyacid synthase, AHAS, EC 2.2.1.6)两个活性位点的晶体结构,以甲基咪草烟为母体,设计合成了8个同簇二效价化合物。经生物活性研究发现:当用不同烷基链连接成簇合物后,其对AHAS的离体活性显著下降。然而,这些簇合物对油菜根长的抑制却表现出与单体相同的活性。
2、基于乙酰胆碱酯酶(acetylcholinesterase, AChE, EC 3.1.1.7)催化活性中心和芳香通道疏水性结合位点的特征,设计合成了31个异簇化合物。经生物活性研究发现:化合物B10,B11,B25,B26,B28和B29对家蝇头部AChE的抑制活性高于母体化合物苯基N-甲基氨基甲酸酯(MH)。其中,簇合物B29显示出最高的活性,比母体化合物提高62倍,比商品化杀虫剂速灭威提高12倍。由此表明,簇合物B29在苯基氨基甲酸酯基团结合到AChE的催化活性中心的同时,苯氧基团能够与芳香峡谷通道疏水性位点结合,提高对AChE的抑制活性,进一步证实了簇合效应在新农药创制中的可行性。
第二部分:利用类同法合成新型吡唑类除草剂。
1、利用类同合成法,以即将上市的农药新品种pyroxasulfone为模板,设计合成了14个新型吡唑类化合物。经生物活性研究发现:在100μg mL-1浓度下,化合物C1-C6明显抑制稗草、马唐和马齿苋芽和根的生长。温室盆栽实验结果表明这些化合物对单子叶杂草具有很好的抑制作用,其活性明显好于对照药剂异丙甲草胺。其中化合物C4显示出最好的除草活性和作物安全性。在玉米田苗前土壤处理实验中,化合物C4能有效的防除马唐等一年生禾本科杂草和部分阔叶杂草,其除草活性好于异丙甲草胺;而且对玉米的生长没有不良影响。可见,化合物C4具有很好的除草活性和选择性,可作为除草剂候选化合物进行进一步的研究。
2、利用活性基团拼接法,设计合成了31个含炔基、嘧啶和吡唑三个活性基团的新型化合物,并测定其除草活性。经生物活性研究发现:目标化合物对马唐、稗草和油菜都具有不同程度的抑制作用。D13-16,D18,D21,D22,和D24表现出很好的白化作用,使测试植物出现白化后死亡,具有进一步研究的价值。
Pesticide is an important guarantee for agricultural production and plays an important role in national economic development. New pesticidal varieties with high activity, low toxicity and safety have been a trend in the 21st century. To find novel compounds with pesticidal activities, we have synthesized 4 novel series of compounds by the methods of cluster effect and me-too, and evaluated their bioactivities in this study. It mainly contains two parts as bellow:
Part I: Synthesis of dual binding site inhibitors by cluster effect
1、Based on the two binding sites of AHAS, 8 symmetrical bivalent molecules of imazapic were designed and synthesized. The preliminary bioassay results showed that the inhibition rate to the AHAS from dimeric compounds were less potent than that of imazapic. And the inhibition rate to the growth of rape (Brassica campestris L.) root from bivalent compounds were very close to that of imazapic at the concentration of 100μg mL-1.
2、Based on catalytic triad and hydrophobic sites of AChE, 31 dimeric compounds were designed and synthesized. Their activities results in vitro showed that compounds B10,B11,B25,B26,B28 and B29 had better AChE inhibitory activities than pheny N-methylcarbamate (MH). Among them, compound B29 displayed the best AChE inhibitory activity with 62-fold higher than MH and 12-fold higher than metolcarb, which suggested that the phenoxy group bound strongly to the residues lining the gorge, the phenyl carbamate group bound at the catalytic sites. The results obtained from these studies demonstrated the feasibility of the cluster effect in the pesticide field.
Part II: Synthesis of the novel pyrazole derivatives by me-too method.
1、Using new pesticide pyroxasulfone, currently under commercial development, as lead compound, 14 novel compounds were designed and synthesized. The herbicidal bioassay results showed that these pyrazole derivatives (C1-C6) inhibited root and shoot elongation of the germinated seed of Echinochloa crusgalli L., Digitaria sanguinalis L., and Portulaca oleracea L. at the concentration of 100μg mL-1. In greenhouse conditions, compounds C1-C6 showed better herbicidal activities against monocotyledonous weeds in pre-emergence treatment than metolachlor. Among them, compound C4 showed best inhibitory activity against both dicotyledonous and monocotyledonous weeds with good safety to maize and rape. Field trials indicated that compound C4 exhibited better herbicidal activity by soil application than the commercial herbicide, metolachlor. Moreover, compound C4 showed the same level of safety to maize as metolachlor. Consequently, compound C4 possessed excellent herbicidal activity and selectivity and deserved further studies as the herbicide candidate in a maize field.
2、By the introduction of alkyne and pyrimidine moieties into pyrazole ring, we have designed and synthesized 31 novel pyrazole derivatives and evaluated their herbicidal activites. The preliminary bioassay results showed these compounds inhibited root and shoot elongation of the germinated seed of Echinochloa crusgalli L., Digitaria sanguinalis L., and rape. Compounds D13-16, D18, D21, D22 and D24 exhibited excellent bleaching herbicidal activities and deserved further studies.
第一部分:利用簇合效应原理合成双作用位点抑制剂
1、基于乙酰乳酸合成酶(acetohydroxyacid synthase, AHAS, EC 2.2.1.6)两个活性位点的晶体结构,以甲基咪草烟为母体,设计合成了8个同簇二效价化合物。经生物活性研究发现:当用不同烷基链连接成簇合物后,其对AHAS的离体活性显著下降。然而,这些簇合物对油菜根长的抑制却表现出与单体相同的活性。
2、基于乙酰胆碱酯酶(acetylcholinesterase, AChE, EC 3.1.1.7)催化活性中心和芳香通道疏水性结合位点的特征,设计合成了31个异簇化合物。经生物活性研究发现:化合物B10,B11,B25,B26,B28和B29对家蝇头部AChE的抑制活性高于母体化合物苯基N-甲基氨基甲酸酯(MH)。其中,簇合物B29显示出最高的活性,比母体化合物提高62倍,比商品化杀虫剂速灭威提高12倍。由此表明,簇合物B29在苯基氨基甲酸酯基团结合到AChE的催化活性中心的同时,苯氧基团能够与芳香峡谷通道疏水性位点结合,提高对AChE的抑制活性,进一步证实了簇合效应在新农药创制中的可行性。
第二部分:利用类同法合成新型吡唑类除草剂。
1、利用类同合成法,以即将上市的农药新品种pyroxasulfone为模板,设计合成了14个新型吡唑类化合物。经生物活性研究发现:在100μg mL-1浓度下,化合物C1-C6明显抑制稗草、马唐和马齿苋芽和根的生长。温室盆栽实验结果表明这些化合物对单子叶杂草具有很好的抑制作用,其活性明显好于对照药剂异丙甲草胺。其中化合物C4显示出最好的除草活性和作物安全性。在玉米田苗前土壤处理实验中,化合物C4能有效的防除马唐等一年生禾本科杂草和部分阔叶杂草,其除草活性好于异丙甲草胺;而且对玉米的生长没有不良影响。可见,化合物C4具有很好的除草活性和选择性,可作为除草剂候选化合物进行进一步的研究。
2、利用活性基团拼接法,设计合成了31个含炔基、嘧啶和吡唑三个活性基团的新型化合物,并测定其除草活性。经生物活性研究发现:目标化合物对马唐、稗草和油菜都具有不同程度的抑制作用。D13-16,D18,D21,D22,和D24表现出很好的白化作用,使测试植物出现白化后死亡,具有进一步研究的价值。
Pesticide is an important guarantee for agricultural production and plays an important role in national economic development. New pesticidal varieties with high activity, low toxicity and safety have been a trend in the 21st century. To find novel compounds with pesticidal activities, we have synthesized 4 novel series of compounds by the methods of cluster effect and me-too, and evaluated their bioactivities in this study. It mainly contains two parts as bellow:
Part I: Synthesis of dual binding site inhibitors by cluster effect
1、Based on the two binding sites of AHAS, 8 symmetrical bivalent molecules of imazapic were designed and synthesized. The preliminary bioassay results showed that the inhibition rate to the AHAS from dimeric compounds were less potent than that of imazapic. And the inhibition rate to the growth of rape (Brassica campestris L.) root from bivalent compounds were very close to that of imazapic at the concentration of 100μg mL-1.
2、Based on catalytic triad and hydrophobic sites of AChE, 31 dimeric compounds were designed and synthesized. Their activities results in vitro showed that compounds B10,B11,B25,B26,B28 and B29 had better AChE inhibitory activities than pheny N-methylcarbamate (MH). Among them, compound B29 displayed the best AChE inhibitory activity with 62-fold higher than MH and 12-fold higher than metolcarb, which suggested that the phenoxy group bound strongly to the residues lining the gorge, the phenyl carbamate group bound at the catalytic sites. The results obtained from these studies demonstrated the feasibility of the cluster effect in the pesticide field.
Part II: Synthesis of the novel pyrazole derivatives by me-too method.
1、Using new pesticide pyroxasulfone, currently under commercial development, as lead compound, 14 novel compounds were designed and synthesized. The herbicidal bioassay results showed that these pyrazole derivatives (C1-C6) inhibited root and shoot elongation of the germinated seed of Echinochloa crusgalli L., Digitaria sanguinalis L., and Portulaca oleracea L. at the concentration of 100μg mL-1. In greenhouse conditions, compounds C1-C6 showed better herbicidal activities against monocotyledonous weeds in pre-emergence treatment than metolachlor. Among them, compound C4 showed best inhibitory activity against both dicotyledonous and monocotyledonous weeds with good safety to maize and rape. Field trials indicated that compound C4 exhibited better herbicidal activity by soil application than the commercial herbicide, metolachlor. Moreover, compound C4 showed the same level of safety to maize as metolachlor. Consequently, compound C4 possessed excellent herbicidal activity and selectivity and deserved further studies as the herbicide candidate in a maize field.
2、By the introduction of alkyne and pyrimidine moieties into pyrazole ring, we have designed and synthesized 31 novel pyrazole derivatives and evaluated their herbicidal activites. The preliminary bioassay results showed these compounds inhibited root and shoot elongation of the germinated seed of Echinochloa crusgalli L., Digitaria sanguinalis L., and rape. Compounds D13-16, D18, D21, D22 and D24 exhibited excellent bleaching herbicidal activities and deserved further studies.
引文
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