利用簇合效应和亚结构拼接法设计合成新农药先导分子的研究
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摘要
本文利用簇合效应和亚结构拼接法，设计合成了3个系列共计134个结构新颖的化合物，同时进行了生物活性评价并对部分高活性化合物进行了初步的作用机理研究。
1、利用乙酰胆碱酯酶（Acetylcholinesterase, AChE, EC3.1.1.7）具有催化中心和外周位点双活性中心特征以及簇合效应原理，设计合成了40个二效价有机磷类簇合物，通过1H NMR、元素分析和质谱对目标物进行了结构确认，并对其离体和活体活性进行测定。试验结果表明：大部分化合物都具有较好的的乙酰胆碱酯酶抑制活性，其中Opal6，Ophal7，Opnl9，Ophnl8在对应的结构中活性最高，Opnl9在此类有机磷簇合物中具有最高的活性，对果蝇的乙酰胆碱酯酶抑制中浓度为23nM，是商品化药剂氧化乐果抑制活性的244倍之多。基于其出色的乙酰胆碱酯酶抑制活性，对部分高活性化合物进行了分子模拟对接研究，模拟结果显示，簇合物的两部分分别结合到乙酰胆碱酯酶的催化中心和外周位点。
2、利用亚结构拼接法，设计合成了32个结构新颖的噻唑类化合物，并进行活性研究。温室盆栽试验结果表明：在300g.a. i. ha~(-1)剂量下， SZ-14和SZ-19对稗草和马齿苋鲜重抑制率超过60%，且SZ-14对牛筋草有较好的抑制作用，同时对玉米和油菜安全。噻唑类化合物的抑菌活性试验表明：这类化合物具有广泛的杀菌活性，其中SZ-20对水稻纹枯的EC50为11.87g/mL，SZ-22对水稻立枯的EC50值为17.06g/mL。综合对比SZ系列化合物的结构特征，噻唑的4-位为氢，5-位为亚甲基桥时拥有较高的生物活性。其中2-位取代基为供电子效应时，表现出更高的除草活性，吸电子取代基则表现为更强的杀菌活性。
3、利用亚结构拼接法，在保留氯虫苯甲酰胺吡唑酸部分的基础上，引入具有广泛生物活性的肟酯类结构，设计合成了62个吡唑酸肟酯类化合物。并进行活性测定。杀虫活性结果表明：PN系列化合物对鳞翅目害虫甜菜夜蛾的活性优于小菜蛾，其中PN58对甜菜夜蛾活性最好，EC50为39.4g/mL。 PN系列化合物具有很好的杀蚜活性，其中PN-56效果最好，致死中浓度为22.46g/mL。 PN系列化合物的杀菌活性结果表明：此系列化合物具有很好的杀菌活性，其中PN8对水稻立枯表现出最好的抑菌活性，其抑制中浓度为10.70g/mL。
Using two different approaches of pesticide discovery,4novel series of compounds were designedand synthesized, and their bioactivities were evaluated in this paper. The studies of mechanism of actionto the higher active compounds were done.
1、 Based on the dual-site structure character of acetylcholinesterase (AChE),40bivalentorganophosphorous compounds were designed and synthesized. Their structures were confirmed by1HNMR and elementary analysis. They were tested in vitro for inhibitory activity of AChE, their resultsshowed that compounds Opal6，Ophal7，Opnl9，Ophnl8had better AChE inhibitory activities, Thecompound Opnl9showed the excellent inhibitor activity to Drosophila melanogasteracetylcholinesterase (DmAChE) with the corresponding value of the IC50of23nM. Its activity was upto245to the positive control omethoate. The molecular docking study showed Opnl9contained favoritespacer bind to the catalytic centers and peripheral site Simultaneously,which highly improved the inhibitpotency of DmAChE.
2、According to substurcture combination,32novel thiazole compounds were designed andsynthesized and systematically evaluated for their bioactivity. By pot-planting method, the bioassayresults showed compounds SZ-14and SZ-19had60%inhibition rate of fresh weight growth ofEchinochloa crusgalli L. and Portulaca oleracea L. at the dose of300g.a.i.ha~(-1), the SZ-14was safe tocorn and rape. All the synthesized compounds displayed a wide range of fungicidal activity, of whichcompounds SZ-20displayed strong growth inhibition of Rhizoctonia solani with EC50of11.87g/mL,and SZ-22against Rhizoctonia solani Khn with EC50of17.06g/mL. Structure activity relationship(SAR) data of these compounds are as follows:1)4-H and5-methylene in the thiazole ring can help toincrease activity;2) compounds with electrondonating substituents on the2-position in the thiazole ringshowed higher herbicidal activity, while compounds with electron-withdrawing substituents performedfungicidal activity.
3、 By the introduction of oxime ester structure to chlorantraniliprole pyrazole acid moiety based onthe substurcture combination, a series of62pyrazole acid oxime ester derivatives were synthesized andsystematically tested for their bioactivity. All the synthesized compounds displayed higher activitiesagainst Spodoptera exigua Hiibner than Plutella xylostella, among which PN58was the most activecompound against Spodoptera exigua Hiibner with LD50values of39.4g/mL. These compounds alsodisplayed well activity against aphids, and PN56is the best with LD50values of22.46g/mL. All thesynthesized compounds were excellent, PN8was the most active compound against Rhizoctonia solaniKhn with EC50values of10.70g/mL.
1、利用乙酰胆碱酯酶（Acetylcholinesterase, AChE, EC3.1.1.7）具有催化中心和外周位点双活性中心特征以及簇合效应原理，设计合成了40个二效价有机磷类簇合物，通过1H NMR、元素分析和质谱对目标物进行了结构确认，并对其离体和活体活性进行测定。试验结果表明：大部分化合物都具有较好的的乙酰胆碱酯酶抑制活性，其中Opal6，Ophal7，Opnl9，Ophnl8在对应的结构中活性最高，Opnl9在此类有机磷簇合物中具有最高的活性，对果蝇的乙酰胆碱酯酶抑制中浓度为23nM，是商品化药剂氧化乐果抑制活性的244倍之多。基于其出色的乙酰胆碱酯酶抑制活性，对部分高活性化合物进行了分子模拟对接研究，模拟结果显示，簇合物的两部分分别结合到乙酰胆碱酯酶的催化中心和外周位点。
2、利用亚结构拼接法，设计合成了32个结构新颖的噻唑类化合物，并进行活性研究。温室盆栽试验结果表明：在300g.a. i. ha~(-1)剂量下， SZ-14和SZ-19对稗草和马齿苋鲜重抑制率超过60%，且SZ-14对牛筋草有较好的抑制作用，同时对玉米和油菜安全。噻唑类化合物的抑菌活性试验表明：这类化合物具有广泛的杀菌活性，其中SZ-20对水稻纹枯的EC50为11.87g/mL，SZ-22对水稻立枯的EC50值为17.06g/mL。综合对比SZ系列化合物的结构特征，噻唑的4-位为氢，5-位为亚甲基桥时拥有较高的生物活性。其中2-位取代基为供电子效应时，表现出更高的除草活性，吸电子取代基则表现为更强的杀菌活性。
3、利用亚结构拼接法，在保留氯虫苯甲酰胺吡唑酸部分的基础上，引入具有广泛生物活性的肟酯类结构，设计合成了62个吡唑酸肟酯类化合物。并进行活性测定。杀虫活性结果表明：PN系列化合物对鳞翅目害虫甜菜夜蛾的活性优于小菜蛾，其中PN58对甜菜夜蛾活性最好，EC50为39.4g/mL。 PN系列化合物具有很好的杀蚜活性，其中PN-56效果最好，致死中浓度为22.46g/mL。 PN系列化合物的杀菌活性结果表明：此系列化合物具有很好的杀菌活性，其中PN8对水稻立枯表现出最好的抑菌活性，其抑制中浓度为10.70g/mL。
Using two different approaches of pesticide discovery,4novel series of compounds were designedand synthesized, and their bioactivities were evaluated in this paper. The studies of mechanism of actionto the higher active compounds were done.
1、 Based on the dual-site structure character of acetylcholinesterase (AChE),40bivalentorganophosphorous compounds were designed and synthesized. Their structures were confirmed by1HNMR and elementary analysis. They were tested in vitro for inhibitory activity of AChE, their resultsshowed that compounds Opal6，Ophal7，Opnl9，Ophnl8had better AChE inhibitory activities, Thecompound Opnl9showed the excellent inhibitor activity to Drosophila melanogasteracetylcholinesterase (DmAChE) with the corresponding value of the IC50of23nM. Its activity was upto245to the positive control omethoate. The molecular docking study showed Opnl9contained favoritespacer bind to the catalytic centers and peripheral site Simultaneously,which highly improved the inhibitpotency of DmAChE.
2、According to substurcture combination,32novel thiazole compounds were designed andsynthesized and systematically evaluated for their bioactivity. By pot-planting method, the bioassayresults showed compounds SZ-14and SZ-19had60%inhibition rate of fresh weight growth ofEchinochloa crusgalli L. and Portulaca oleracea L. at the dose of300g.a.i.ha~(-1), the SZ-14was safe tocorn and rape. All the synthesized compounds displayed a wide range of fungicidal activity, of whichcompounds SZ-20displayed strong growth inhibition of Rhizoctonia solani with EC50of11.87g/mL,and SZ-22against Rhizoctonia solani Khn with EC50of17.06g/mL. Structure activity relationship(SAR) data of these compounds are as follows:1)4-H and5-methylene in the thiazole ring can help toincrease activity;2) compounds with electrondonating substituents on the2-position in the thiazole ringshowed higher herbicidal activity, while compounds with electron-withdrawing substituents performedfungicidal activity.
3、 By the introduction of oxime ester structure to chlorantraniliprole pyrazole acid moiety based onthe substurcture combination, a series of62pyrazole acid oxime ester derivatives were synthesized andsystematically tested for their bioactivity. All the synthesized compounds displayed higher activitiesagainst Spodoptera exigua Hiibner than Plutella xylostella, among which PN58was the most activecompound against Spodoptera exigua Hiibner with LD50values of39.4g/mL. These compounds alsodisplayed well activity against aphids, and PN56is the best with LD50values of22.46g/mL. All thesynthesized compounds were excellent, PN8was the most active compound against Rhizoctonia solaniKhn with EC50values of10.70g/mL.
引文
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