含异噁唑基的酰基硫脲及其环化产物的设计，合成及除草活性
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摘要
乙酰乳酸合成酶(ALS)抑制剂具有生物活性高,杀草谱广,对人和动物安全等特性,成为杂草防除技术发展中的一大突破。随着ALS抑制剂面临的抗药性问题越来越突出,以ALS为靶标,寻找超高效、低毒、除草谱广的目标化合物,已经成为化学和农药界研究的热点之一。
含嘧啶环的酰基硫脲及其环化产物2H-1,2,4-噻二唑并[2,3-a]嘧啶等化合物容易与杂草中乙酰乳酸合成酶活性中心的氨基酸残基形成氢键和疏水作用力,该酶活性降低或者丧失,阻断支链氨基酸的生物合成。本文以生物活性分子设计理论为指导,设计合成了2个系列以ALS为靶标的目标化合物,并对其进行了活体除草活性筛选,主要研究内容和结果如下:
1.分别从2,4-二氯苯甲醛、4-三氟甲基苯甲醛出发,经肟化、氯代、成环、水解、酰氯化、异硫氰酸酯化、亲核加成等7步反应,合成了一系列结构新颖含异噁唑环的嘧啶基酰基硫脲类化合物: 16种N-(4,6-二取代嘧啶-2-基)-N′-[5-甲基-3-取代苯基异噁唑-4-甲酰基]硫脲4_a～4_p,用Br2作氧化剂,将上述酰基硫脲氧化环化,得到另一系列结构新颖的稠杂环衍生物: 16种5,7-二取代-2-[5-甲基-3-(取代苯基异噁唑-4-甲酰亚胺]-2H-1,2,4-噻二唑并[2, 3-a]嘧啶5_a～5_p。目标化合物的结构经红外光谱、核磁共振氢谱及元素分析确证。
2.以单子叶植物(稗草、马唐),双子叶植物(小藜、油菜)为试材,精噁唑禾草灵为对照药剂,对目标化合物进行了室内除草活性评价。初步测定结果表明:2个系列目标化合物都表现出一定的抑制活性,且对根长的抑制大于对茎长的抑制,对双子叶植物的抑制大于对单子叶植物的抑制。其中,5,7-二取代-2-[5-甲基-3-(4-三氟甲基苯基)异噁唑-4-甲酰亚胺)]-2H-1,2,4-噻二唑并[2,3-a]嘧啶5_a～5_h的抑制活性较高, 100 mg/L浓度下对油菜根长的抑制率在75 %以上,5,7-二取代-2-[5-甲基-3-(2,4-二氯苯基)异噁唑-4-甲酰亚胺]-2H-1,2,4-噻二唑并[2,3-a]嘧啶5i～5_p对油菜根长的抑制率在70 % ~ 75 %,高于对照药剂。N-(4,6-二取代嘧啶-2-基)-N′-[5-甲基-3-(4-三氟甲基苯基)异噁唑-4-甲酰基]硫脲4_i～4_p与N-(4,6-二取代嘧啶-2-基)-N′-[5-甲基-3-(2,4-二氯苯基)异噁唑-4-甲酰基]硫脲4_a～4h抑制活性相对较好,在100 mg/L浓度下有中等除草活性,对油菜根长的抑制率均在55 % ~ 60 %。
3.对目标化合物4i进行了X射线单晶衍射实验,研究表明,该化合物属于三斜晶系,空间群为P-1,晶胞参数: a = 7.351(6) (?), b = 10. 373(10)(?), c = 14.120(12) (?),α= 72.222(14)°,β= 85.372(15)°,γ= 85. 380 (14)°, V = 1020.1(16)(?)3, Z = 2, Dcalcd. = 1.418 g·cm~(-3),μ= 0.211mm–l, F(000) = 448。硫脲桥上的氮原子与嘧啶环上的氮原子以分子内氢键N-H…N形式形成了稳定的六元环。
4.初步探讨了目标分子结构与除草活性的关系,生测研究结果表明,苯环邻对位连有吸电子取代基,以及嘧啶环4, 6位是甲基或甲氧基等供电子基,对提高目标化合物的除草活性是必要的。
Acetolactate synthase (ALS) inhibitors exhibit high biological activities, broad herbicidal spectrum and other features, and have become a major breakthrough in weed control technology. However, ALS inhibitor are facing more and more prominent drug-resistance problem. Therefore, targeting on acetolactate synthase, to find novel compounds with super-efficient, low toxicity, broad spectrum properties, has become focus in the field of chemical and pesticide.
Pyrimidinyl acylthiourea and 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine have been reported to form hydrogen bonds and hydrophobic interactions easily with amino acid residues of active center of ALS, activity of ALS is decreased or lost and biosynthesis of branch-chain amino acid is blocked. In view of this, two series of novel compounds targeting on ALS were designed and synthesized, and their herbicidal activities in vitro were screened. Main work and results were listed as follows:
1. A series of novel heterocyclic pyrimidinyl acylthiourea: sixteen N-[5-methyl-3-substitu tedphenyl)isoxazolyl-4-yl]acyl-N'-(4,6-disubstitutedpyrimidin-2-yl) thioureas were synthesi zed from 2,4-chlorobenzaldehyde or 4-trifluoromethylbenzaldehyde (starting materials) in multi-steps; Another series of novel fused heterocyclic compound: sixteen 5,7-disubstituted -2-[5-methyl-3-substitutedphenylIsoxazolyl-4-formylimino]-2H-1,2,4- thiadiazolo [2, 3-a] pyrimidine were prepared from corresponding acyl thioureas by employing bromine as oxid ant. Structures of target compounds were confirmed by IR, 1H NMR and elemental analysis, their physical, chemical properties and spectral properties have also been analyzed and discu ssed.
2. Preliminary herbicidal activities evaluation of target compound was performed accord ing to bioassay standard method, the culture dish method. Monocotyledon (Echinochloa crusgalli L, Digitaria ciliaris L), Dicotyledons (Chenopodium serotinum L, Brassica napus L) was employed as materials, fenoxaprop-p-ethyl as controlling herbicide. Results indicate d that two series of target compounds showed cartain inhibitory activity, inhibition of root length is greater than that of stalk length, and inhibi tion of dicotyledons is higher than that of monocotyledons in general; 5,7-disubstituted-2-[5-methyl-3- (4-trifluoromethylphenyl) Isoxazolyl-4-formylimino]-2H-1,2,4-thiadiazolo[2,3-a]pyrimidine 5i～5_p exhibited highest activity with inhibitory rate towards root length of Brassica napus L. more than 75 % at a higher dose of 100mg/L, 5,7-disubstituted-2-[5-methyl-3-(2,4-dichloro phenyl) Isoxazolyl-4-formylimino]-2H-1,2,4-thiadiazole [2,3-a] pyrimidine 5_a～5_h exhibited higher activity with inhibitory rate towards root length of Chenopodium serotinum L. in the range of 70 % to 75 % at a higher concentration of 100mg/ L, higher than the controling; N-[5-methyl-3-(4-trifluoromethyl phenyl)Isoxazolyl-4-yl]acyl-N'-(4,6-disubstitutedpyrimidin-2-yl) thioure as 4i～4_p and N-[5-methyl-3-(2,4-dichlorophenyl) Isoxazolyl-4-yl]acyl-N'-(4, 6-disubstitu ted pyrimidin-2-yl) thioureas 4_a～4h showed relatively high inhibitory activity at the conce ntration of 100 mg/L, inhibition rate towards root length of Brassica napus L. in the range of 50 % to 55 %, some of these compounds showed certain plant growth regulat ing activity, which can promote growth of root at low concentration (10 mg/L).
3. Single crystal structure of 4i was determined from single crystal X-ray diffraction data. The crystal belongs to system with space group a = 7.351(6)(?), b = 10.373 (10)(?), c = 14.12 0 (12)(?),α= 72.222(14)°,β= 85.372(15)°,γ= 85.380 (14)°, V = 1020.1 (16) (?)3, Z = 2, Dcalcd.= 1.418 g·cm~(-3),μ= 0.211mml, F(000) = 448. A six-membered ring comes into being between the nitrogen atom on thiourea linkage and the nitrogen atom on pyrimidine ring in the form of intermolecule hydrogen bond N-H…N.
4. Preliminary relationships between structure and activity of target compounds were also analyzed and discussed. Bioassay results indicated it was necessary for improving herbicidal activity of target compounds that the moieties at ortho- and para- positions of phenyl were electron withdrawing groups, while 4,6- positions of pyrimidine ring were electron donor groups (i.g. methyl or methoxy).
含嘧啶环的酰基硫脲及其环化产物2H-1,2,4-噻二唑并[2,3-a]嘧啶等化合物容易与杂草中乙酰乳酸合成酶活性中心的氨基酸残基形成氢键和疏水作用力,该酶活性降低或者丧失,阻断支链氨基酸的生物合成。本文以生物活性分子设计理论为指导,设计合成了2个系列以ALS为靶标的目标化合物,并对其进行了活体除草活性筛选,主要研究内容和结果如下:
1.分别从2,4-二氯苯甲醛、4-三氟甲基苯甲醛出发,经肟化、氯代、成环、水解、酰氯化、异硫氰酸酯化、亲核加成等7步反应,合成了一系列结构新颖含异噁唑环的嘧啶基酰基硫脲类化合物: 16种N-(4,6-二取代嘧啶-2-基)-N′-[5-甲基-3-取代苯基异噁唑-4-甲酰基]硫脲4_a～4_p,用Br2作氧化剂,将上述酰基硫脲氧化环化,得到另一系列结构新颖的稠杂环衍生物: 16种5,7-二取代-2-[5-甲基-3-(取代苯基异噁唑-4-甲酰亚胺]-2H-1,2,4-噻二唑并[2, 3-a]嘧啶5_a～5_p。目标化合物的结构经红外光谱、核磁共振氢谱及元素分析确证。
2.以单子叶植物(稗草、马唐),双子叶植物(小藜、油菜)为试材,精噁唑禾草灵为对照药剂,对目标化合物进行了室内除草活性评价。初步测定结果表明:2个系列目标化合物都表现出一定的抑制活性,且对根长的抑制大于对茎长的抑制,对双子叶植物的抑制大于对单子叶植物的抑制。其中,5,7-二取代-2-[5-甲基-3-(4-三氟甲基苯基)异噁唑-4-甲酰亚胺)]-2H-1,2,4-噻二唑并[2,3-a]嘧啶5_a～5_h的抑制活性较高, 100 mg/L浓度下对油菜根长的抑制率在75 %以上,5,7-二取代-2-[5-甲基-3-(2,4-二氯苯基)异噁唑-4-甲酰亚胺]-2H-1,2,4-噻二唑并[2,3-a]嘧啶5i～5_p对油菜根长的抑制率在70 % ~ 75 %,高于对照药剂。N-(4,6-二取代嘧啶-2-基)-N′-[5-甲基-3-(4-三氟甲基苯基)异噁唑-4-甲酰基]硫脲4_i～4_p与N-(4,6-二取代嘧啶-2-基)-N′-[5-甲基-3-(2,4-二氯苯基)异噁唑-4-甲酰基]硫脲4_a～4h抑制活性相对较好,在100 mg/L浓度下有中等除草活性,对油菜根长的抑制率均在55 % ~ 60 %。
3.对目标化合物4i进行了X射线单晶衍射实验,研究表明,该化合物属于三斜晶系,空间群为P-1,晶胞参数: a = 7.351(6) (?), b = 10. 373(10)(?), c = 14.120(12) (?),α= 72.222(14)°,β= 85.372(15)°,γ= 85. 380 (14)°, V = 1020.1(16)(?)3, Z = 2, Dcalcd. = 1.418 g·cm~(-3),μ= 0.211mm–l, F(000) = 448。硫脲桥上的氮原子与嘧啶环上的氮原子以分子内氢键N-H…N形式形成了稳定的六元环。
4.初步探讨了目标分子结构与除草活性的关系,生测研究结果表明,苯环邻对位连有吸电子取代基,以及嘧啶环4, 6位是甲基或甲氧基等供电子基,对提高目标化合物的除草活性是必要的。
Acetolactate synthase (ALS) inhibitors exhibit high biological activities, broad herbicidal spectrum and other features, and have become a major breakthrough in weed control technology. However, ALS inhibitor are facing more and more prominent drug-resistance problem. Therefore, targeting on acetolactate synthase, to find novel compounds with super-efficient, low toxicity, broad spectrum properties, has become focus in the field of chemical and pesticide.
Pyrimidinyl acylthiourea and 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine have been reported to form hydrogen bonds and hydrophobic interactions easily with amino acid residues of active center of ALS, activity of ALS is decreased or lost and biosynthesis of branch-chain amino acid is blocked. In view of this, two series of novel compounds targeting on ALS were designed and synthesized, and their herbicidal activities in vitro were screened. Main work and results were listed as follows:
1. A series of novel heterocyclic pyrimidinyl acylthiourea: sixteen N-[5-methyl-3-substitu tedphenyl)isoxazolyl-4-yl]acyl-N'-(4,6-disubstitutedpyrimidin-2-yl) thioureas were synthesi zed from 2,4-chlorobenzaldehyde or 4-trifluoromethylbenzaldehyde (starting materials) in multi-steps; Another series of novel fused heterocyclic compound: sixteen 5,7-disubstituted -2-[5-methyl-3-substitutedphenylIsoxazolyl-4-formylimino]-2H-1,2,4- thiadiazolo [2, 3-a] pyrimidine were prepared from corresponding acyl thioureas by employing bromine as oxid ant. Structures of target compounds were confirmed by IR, 1H NMR and elemental analysis, their physical, chemical properties and spectral properties have also been analyzed and discu ssed.
2. Preliminary herbicidal activities evaluation of target compound was performed accord ing to bioassay standard method, the culture dish method. Monocotyledon (Echinochloa crusgalli L, Digitaria ciliaris L), Dicotyledons (Chenopodium serotinum L, Brassica napus L) was employed as materials, fenoxaprop-p-ethyl as controlling herbicide. Results indicate d that two series of target compounds showed cartain inhibitory activity, inhibition of root length is greater than that of stalk length, and inhibi tion of dicotyledons is higher than that of monocotyledons in general; 5,7-disubstituted-2-[5-methyl-3- (4-trifluoromethylphenyl) Isoxazolyl-4-formylimino]-2H-1,2,4-thiadiazolo[2,3-a]pyrimidine 5i～5_p exhibited highest activity with inhibitory rate towards root length of Brassica napus L. more than 75 % at a higher dose of 100mg/L, 5,7-disubstituted-2-[5-methyl-3-(2,4-dichloro phenyl) Isoxazolyl-4-formylimino]-2H-1,2,4-thiadiazole [2,3-a] pyrimidine 5_a～5_h exhibited higher activity with inhibitory rate towards root length of Chenopodium serotinum L. in the range of 70 % to 75 % at a higher concentration of 100mg/ L, higher than the controling; N-[5-methyl-3-(4-trifluoromethyl phenyl)Isoxazolyl-4-yl]acyl-N'-(4,6-disubstitutedpyrimidin-2-yl) thioure as 4i～4_p and N-[5-methyl-3-(2,4-dichlorophenyl) Isoxazolyl-4-yl]acyl-N'-(4, 6-disubstitu ted pyrimidin-2-yl) thioureas 4_a～4h showed relatively high inhibitory activity at the conce ntration of 100 mg/L, inhibition rate towards root length of Brassica napus L. in the range of 50 % to 55 %, some of these compounds showed certain plant growth regulat ing activity, which can promote growth of root at low concentration (10 mg/L).
3. Single crystal structure of 4i was determined from single crystal X-ray diffraction data. The crystal belongs to system with space group a = 7.351(6)(?), b = 10.373 (10)(?), c = 14.12 0 (12)(?),α= 72.222(14)°,β= 85.372(15)°,γ= 85.380 (14)°, V = 1020.1 (16) (?)3, Z = 2, Dcalcd.= 1.418 g·cm~(-3),μ= 0.211mml, F(000) = 448. A six-membered ring comes into being between the nitrogen atom on thiourea linkage and the nitrogen atom on pyrimidine ring in the form of intermolecule hydrogen bond N-H…N.
4. Preliminary relationships between structure and activity of target compounds were also analyzed and discussed. Bioassay results indicated it was necessary for improving herbicidal activity of target compounds that the moieties at ortho- and para- positions of phenyl were electron withdrawing groups, while 4,6- positions of pyrimidine ring were electron donor groups (i.g. methyl or methoxy).
引文
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