【作者】 陈敏；

【导师】 杨春龙；

【作者基本信息】 南京农业大学 ， 农药学， 2011， 硕士

【摘要】 1,2,4-三氮唑和1,3,4-噁二唑同属含氮五元杂环,其衍生物常常表现出良好的抗真菌、抗癌、抗肿瘤、杀虫及除草等生物活性,其中不少化合物已被开发利用,在植物保护中发挥了重要作用。本文在合成13个4-氨基-5-取代-4H-1,2,4-三氮唑-3-硫醇和21个5-取代-1,3,4-噁二唑-2-硫醇两个系列化合物的基础上,设计并合成了12个氟代3,5-二取代-4H-1,2,4-三氮唑-4-胺类化合物,并以其中杀菌活性突出的化合物即5-(2-甲基苯基)-1,3,4-噁二唑-3-硫醇为先导化合物,对其巯基进行进一步修饰,设计并合成了7类总计40个新型5-(2-甲基苯基)-1,3,4-嗯二唑类衍生物,同时进行了杀菌活性测定和初步的构效关系分析,为进一步研究和筛选新型嗯二唑类杀菌剂提供依据。以羧酸为原料合成了13个4-氨基-5-取代-4H-1,2,4-三氮唑-3-硫醇(3和8a-l)和21个5-取代-1,3,4-嗯二唑-2-硫醇化合物(9a-u)。采用IR、1HNMR、MS和元素分析确证了各化合物的结构。测定了各化合物对小麦赤霉病菌(1Fusarium graminearum)、蔬菜灰霉病菌(Botrytis cinerea)、小麦纹枯病菌(Rhizoctonia cerealis)和辣椒炭疽病菌(Colletotrichum capsici)的抑菌活性。结果显示,化合物3和8a-l在100μg/mL浓度下对供试真菌均有一定的抑制活性,其中化合物8f的活性最高,对蔬菜灰霉病菌、小麦纹枯病菌和辣椒炭疽病菌的抑制率分别达到了77.5%、51.0%和67.9%。化合物9a-u在50μg/mL浓度下的抑菌活性更加显著,其中化合物9b、9d、9e和9q最为突出,化合物9d和9q对蔬菜灰霉病菌的抑制率达到94.7%和94.2%,在5位取代基相同的情况下,嗯二唑硫醇类化合物的杀菌活性高于三氮唑硫醇类化合物,尤其是5位为取代苯环时的嗯二唑硫醇杀菌活性较为突出。以氟代4-氨基-5-取代-4H-1,2,4-三氮唑-3-硫醇为原料,合成了12个氟代3,5-.二取代-4H-1,2,4-三氮唑-4-胺类化合物(12a-j、13和14)。化合物的结构经IR、1H NMR、19F NMR、MS和元素分析确证,化合物12g和13通过x-单晶衍射分析得到进一步确证。100μg/mL浓度下的抑菌活性测定表明,目标化合物对供试真菌有一定的抑制作用,其中化合物12e-i及14对水稻纹枯病菌的抑制率均超过50%,化合物12f对小麦纹枯病菌、化合物14对辣椒炭疽病菌的抑制率也超过了50%。分析表明,三氮唑5位连接有氟代苯基时的抑菌活性高于连接三氟甲基的活性,但如3位连有苯基,5位连接三氟甲基时也有较好的活性。以5-邻甲基-1,3,4-噁二唑-2-硫醇为原料,合成了7类共40个5-(2-甲基苯基)-1,3,4-噁二唑-2-硫醇的衍生物,包括10个2-取代亚磺酰基-5-(2-甲基苯基)-1,3,4-噁二唑(16a-j)、10个2-取代磺酰基-5-(2-甲基苯基)-1,3,4-噁二唑(17a-j)、5个2-取代苯氧基-5-(2-甲基苯基)-1,3,4-噁二唑(18a-e)、4个2-取代苯硫基-5-(2-甲基苯基)-1,3,4-噁二唑(19a-d)、1个4-(5-(2-甲基苯基)-1,3,4-噁二唑-2-基)吗啉(20)、5个N’-(2-甲基苯甲酰基)胺-1-碳酰肼(22a-e)及5个3-烃基-5-(2-甲基苯基)-1,3,4-噁二唑-2(3H)-酮(23a-e)。采用IR、1H NMR、MS、元素分析并结合化合物22a和23a的X-单晶衍射分析确证了目标化合物的结构。100μg/mL浓度下的抑菌活性测定表明,亚砜类化合物(16a-e和16h-j)、砜类化合物(17a-e和17h-j)、芳香硫醚类化合物(19a-d)和噁二唑酮类化合物(21、23a-d)的活性较好。对抑制率较高的化合物(9b,15a-d,16a-d,17a-d和21)EC50测定结果显示,17a的活性最高,对小麦赤霉病菌、蔬菜灰霉病菌、小麦纹枯病菌和辣椒炭疽病菌的EC50值分别达到6.3μg/mL、5.6μg/mL、1.7μg/mL和11.5μg/mL。初步构效关系分析表明,5-(2-甲基苯基)-1,3,4-噁二唑2位连接短链烷基磺酰基的化合物杀菌活性最好,高于相应的亚磺酰基和硫醚类化合物的活性,烃基的碳链延长活性降低。2位为烷基硫基取代的化合物活性高于芳香硫醚类化合物的活性,而芳香硫醚的活性优于芳香醚。当噁二唑开环变成碳酰肼后,化合物的活性降低。5-(2-甲基苯基)-1,3,4-噁二唑-2(3H)-酮及其衍生物的活性与5-(2-甲基苯基)-1,3,4-噁二唑-2-硫醇的活性相当。更多还原

【Abstract】 1,2,4-Triazole and1,3,4-oxadiazole were two kinds of nitrogen containing five-member heterocycle. Their derivatives showed excellent bioactivities include fungicidal, antitumor, insecticidal and herbicidal activities. In this article,4-amine-5-substituted-4H-1,2,4-triazol-3-thiol,5-substiuted-1,3,4-oxadiazol-2-thiol and their derivatives were designed and synthesized, their fungicide activities were determined and the preliminary structure-activity relationship was analysed.Different carboxylic acids were used as starting materials to synthesize thirteen4-amine-5-substituted-4H-1,2,4-triazol-3-thiols(3and8a-1) and twenty-one5-substiuted-1,3,4-oxadiazol-2-thiols(9a-u) via a facile four-step procedure including esterification, hydrazination, salt formation and cyclization. All the compounds were characterized using IR,1H NMR, MS and elemental analysis. The preliminary bioassay results showed that these compounds exhibited certain fungicidal activities against Fusarium graminearum, Botrytis cinerea, Rhizoctonia cerealis and Colletotrichum capsici at the concentration of100μg/mL for the compounds3and8a-I and50μg/mL for the compounds9a-u. The preliminary structure-activity relationship revealed that, when having the same substituent group at the5-position of the nitrogen heterocycle, he compounds9a-u always showed better fungicidal activities than the compounds3and8a-1.Espectically, the compounds9with phenyl groups at the5-position echibited better fungicidal activities than with other aromatic groups.The4-amine-5-(fluorinated substituted)-4H-1,2,4-triazole-3-thiols were used as raw materials to synthesize twelve fluorined3,5-disubstituted-4H-1,2,4-triazol-4-amines(12a-j,13and14). The structures of these compounds were well supported by spectroscopic data, elemental analysis and single crystal X-ray diffraction analysis on compounds12g and13. The antifungal bioassay results demonstrated that these title compounds showed different fungicidal activities at the concentration of100μg/mL. The structure-activity relationship analysis revealed that introducing the fluorinated phenyl, especial the4-trifluoromethyl phenyl group, at the5-position of1,2,4-triazol-4-amine, or introducing the phenyl group at the3-position while the trifluoromethyl group was connected at the5-position directly were helpful to improve the fungicidal activities.The compound9b was used as a leading compound for its good fungicidal activities to designe and synthesize405-o-tolyl-1,3,4-oxadiazole-2-thiol derivates, including ten2-alkylsulfinyl-5-o-tolyl-1,3,4-oxadiazoles(16a-j), ten2-alkylsulfonyl-5-o-tolyl-1,3,4-oxadiazoles(17a-j), five2-(substituted phenoxy)-5-o-tolyl-1,3,4-oxadiazoles(18a-e), four2-(substituted phenylthio)-5-o-tolyl-1,3,4-oxadiazoles(19a-d),4-(5-o-tolyl-1,3,4-oxadiazol-2-yl)morpholine(20), five N’-(2-methylbenzoyl) pyrrolidine-l-carbohydrazides(22a-e) and five3-alkyl-5-o-tolyl-1,3,4-oxadiazol-2(3H)-ones(23a-e). The structures of these compounds were well supported by IR,1H NMR, MS, elemental analysis and single crystal X-ray diffraction analysis on the compounds22a and23a. The preliminary bioassay was performed at the concentration of100μg/mL, the EC50values of some compounds were determined. The compounds16a-e,16h-j,17a-e,17h-j,19a-d,21and23a-d exhibited good fungicidal activities. And the compounds17a showed the highest activity with the EC50values of6.3μg/mL,5.6μg/mL,1.7μg/mL and11.5μg/mL against Fusarium graminearum, Botrytis cinerea, Rhizoctonia cerealis and Colletotrichum capsici, respectively. The structure-activity relationship analysis showed that the alkyls with short chain linked to the2-position of1,3,4-oxadiazole were helpful to improve the fungicidal activities. When the same alkyls were linked to sulfur, the compounds with sulfonyl showed better activities than with sulfinyl.更多还原