1，2，3-噻二唑衍生物的合成、表征及生物活性
摘要
1,2,3-噻二唑类化合物因其广泛的生物活性引起越来越多的关注,尤其是具有系统获得性抗性(Systemic Acquired Resistance, SAR)的1,2,3-噻二唑类植物激活剂苯并噻二唑(BTH)和噻酰菌胺(TDL)的成功商品化极大推进了对其SAR的研究。
本论文通过生物电子等排、活性亚结构拼接和组合化学等原理,设计合成了5个结构类型共128个1,2,3-噻二唑衍生物,其中117个为未见文献报道的新化合物。所有化合物的化学结构通过IR、1~H NMR或~(13)C NMR、HRMS或元素分析的测定,前四类目标化合物的化学结构还各挑选了1个代表性的化合物培养了单晶,并以X-射线单晶衍射法测定了其晶体结构加以确证。本文对合成的所有化合物进行了较为系统的生物活性测定,具体研究内容和结果如下:
第一部分:以4-甲基-1,2,3-噻二唑-5-甲酰氯为中间体,设计合成了23个4-甲基-1,2,3-噻二唑-5-甲酸芳酯化合物,其中12个未见文献报道。生物活性测试结果显示,在50μg/mL下,含有喹啉基和2,6-二氯苯基的目标产物具有广谱的杀菌活性,其EC50值在2.99~28.35μg/mL之间;部分化合物还具有很好的诱导抗烟草花叶病毒(tobacco mosaic virus, TMV)活性。研究结果为创制同时具有杀菌活性和诱导抗病活性的1,2,3-噻二唑类农药先导分子奠定了理论和实践基础。
第二部分:以4-甲基-1,2,3-噻二唑-5-甲酰氯为中间体,设计合成了23个未见文献报道的N-(4-甲基-1,2,3-噻二唑-5-基)-N′-杂环基脲类化合物。生测结果显示,仅化合物Ⅱ-18有一定的芽后除草活性;大部分化合物在50μg/mL下仅对油菜菌核病菌(Sclerotinia sclerotiorum)具有较好的杀菌活性。
第三部分:根据活性亚结构拼接原理,利用4-甲基-1,2,3-噻二唑-5-甲酸乙酯设计合成了33个N-[5-(4-甲基-1,2,3-噻二唑-5-基)-1,3,4-噻二唑-2-基]取代甲酰胺,生物活性测试结果显示,部分化合物在50μg/mL下具有较好的杀菌活性,个别化合物在400μg/mL时对小菜蛾和在5μg/mL时对蚊幼虫具有优异的杀虫活性。
第四部分:以4-甲基-1,2,3-噻二唑-5-甲酸酸为中间体,通过Ugi四组分反应将含氟活性基团4-1,1,2,2-四氟乙氧基-3,5-二氯苯基引入到1,2,3-噻二唑中,设计合成了两个系列共38个未见文献报道的N-(1-取代苯基-2-取代氨基-2-羰基乙基)-N-(3,5-二氯-4-1,1,2,2-四氟乙氧基苯基)-4-甲基-1,2,3-噻二唑-5-甲酰胺,初步生物活性测试结果显示,部分化合物具有较好的杀菌活性以及很好的杀小菜蛾和杀蚊幼虫活性;大部分化合物在500μg/mL和100μg/mL下对烟草花叶病毒显示了不同程度的直接抗病毒活性和很好的钝化和治疗活性。F原子的引入有利于目标分子生物活性的提高。
1,2,3-Thiadiazoles have attracted more and more attention due to their wide spectrum of biological activities. Especially, successfully commercialization of some 1,2,3-thiadiazoles such as tiadinil (TDL) and acibenzolar-S-methyl (BTH) as elicitors accelerated the studies on their synthesis and systemic acquired resistance (SAR).
In this thesis, five types of structures including altogether 128 (117 new compounds) 1,2,3-thiadiazole derivatives were designed and synthesized according to the principles of electronic isosteric, combination of bioactive sub-structure and combinatorial chemistry. All structures synthesized were characterized by IR, 1H NMR or 13C NMR, HRMS spectra or elemental analysis. Four typical crystals of each kind of the title compounds were chosen for culturation and determination of X-ray crystal diffraction for structural confirmation. The biological activities of the title compounds were also systematically determined. The contents and results of the studies are summarized as bellows:
In 1st part, 23 (12 new compounds) 4-methyl-1,2,3-thiadiazole-5- carboxylic acid aryl esters were designed and synthesized by using 4-methyl-1,2,3-thiadiazole-5- carbonyl chloride as an intermediate. The preliminary bioassay results indicated that the title compounds containing quinoline groups possessed a broad spectrum of fungicide activity with EC50 value ranged from 2.99 to 28.35μg/mL; some compounds exhibid good systemic acquired resistance for tobacco against tobacco mosaic virus (TMV) too. The results established basis for development of novel 1,2,3-thiadiazole lead with both fungicide activity and systemic acquired resistance.
In 2nd part, twenty-three new N-(4-methyl-1,2,3-thiadiazol-5-yl)-N′- heterocyclic ureas were designed and synthesized by using 4-methyl-1,2,3-thiadiazole- 5-carbonyl chloride as an intermediate. Bioassay results indicated that only compoundⅡ-18 had moderate post-emergence herbicidal activity; most of the title compounds only presented good fungicide activity against Sclerotinia sclerotiorum at 50μg/mL.
In the 3rd part, thirty-three novel N-[5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4- thiadiazol-2-yl] substituted amides were designed and synthesized according to the principle of combination of bioactive substructure using ethyl 4-methyl-1,2,3- thiadiazole-5-carboxylate as an intermediate. Bioassay results indicated that some title compounds had good fungicide activity at 50μg/mLand excellent insecticidal activity against Plutella xylostella L. at 400μg/mLand excellent larvicidal activity against Culex pipiens pallens at 5μg/mL.
In 4th part, two series including altogether thirty-eight novel 3,5-dichloro-4-(1,1, 2,2-tetrafluoroethoxy) phenyl containing 4-methyl-1,2,3-thiadiazoles were designed and synthesized via Ugi reaction by 4-methyl-1,2,3-thiadiazole-5-carboxylic acid as an intermediate. Bioassay results indicated that some title compounds had good fungicide activity and insecticidal activity, most of the compounds presented a certain degree of direct inhibition activity, good inactivation and curative activity against TMV at 500μg/mLand 100μg/mL, fluorine improved the activity of the title compounds.
The results of these studies indicated that 1,2,3-thiadiazole compounds exhibited various biological activities, and development of novel 1,2,3-thiadiazole lead with both fungicide and systemic acquired resistance had basis in theoretics and practice.
本论文通过生物电子等排、活性亚结构拼接和组合化学等原理,设计合成了5个结构类型共128个1,2,3-噻二唑衍生物,其中117个为未见文献报道的新化合物。所有化合物的化学结构通过IR、1~H NMR或~(13)C NMR、HRMS或元素分析的测定,前四类目标化合物的化学结构还各挑选了1个代表性的化合物培养了单晶,并以X-射线单晶衍射法测定了其晶体结构加以确证。本文对合成的所有化合物进行了较为系统的生物活性测定,具体研究内容和结果如下:
第一部分:以4-甲基-1,2,3-噻二唑-5-甲酰氯为中间体,设计合成了23个4-甲基-1,2,3-噻二唑-5-甲酸芳酯化合物,其中12个未见文献报道。生物活性测试结果显示,在50μg/mL下,含有喹啉基和2,6-二氯苯基的目标产物具有广谱的杀菌活性,其EC50值在2.99~28.35μg/mL之间;部分化合物还具有很好的诱导抗烟草花叶病毒(tobacco mosaic virus, TMV)活性。研究结果为创制同时具有杀菌活性和诱导抗病活性的1,2,3-噻二唑类农药先导分子奠定了理论和实践基础。
第二部分:以4-甲基-1,2,3-噻二唑-5-甲酰氯为中间体,设计合成了23个未见文献报道的N-(4-甲基-1,2,3-噻二唑-5-基)-N′-杂环基脲类化合物。生测结果显示,仅化合物Ⅱ-18有一定的芽后除草活性;大部分化合物在50μg/mL下仅对油菜菌核病菌(Sclerotinia sclerotiorum)具有较好的杀菌活性。
第三部分:根据活性亚结构拼接原理,利用4-甲基-1,2,3-噻二唑-5-甲酸乙酯设计合成了33个N-[5-(4-甲基-1,2,3-噻二唑-5-基)-1,3,4-噻二唑-2-基]取代甲酰胺,生物活性测试结果显示,部分化合物在50μg/mL下具有较好的杀菌活性,个别化合物在400μg/mL时对小菜蛾和在5μg/mL时对蚊幼虫具有优异的杀虫活性。
第四部分:以4-甲基-1,2,3-噻二唑-5-甲酸酸为中间体,通过Ugi四组分反应将含氟活性基团4-1,1,2,2-四氟乙氧基-3,5-二氯苯基引入到1,2,3-噻二唑中,设计合成了两个系列共38个未见文献报道的N-(1-取代苯基-2-取代氨基-2-羰基乙基)-N-(3,5-二氯-4-1,1,2,2-四氟乙氧基苯基)-4-甲基-1,2,3-噻二唑-5-甲酰胺,初步生物活性测试结果显示,部分化合物具有较好的杀菌活性以及很好的杀小菜蛾和杀蚊幼虫活性;大部分化合物在500μg/mL和100μg/mL下对烟草花叶病毒显示了不同程度的直接抗病毒活性和很好的钝化和治疗活性。F原子的引入有利于目标分子生物活性的提高。
1,2,3-Thiadiazoles have attracted more and more attention due to their wide spectrum of biological activities. Especially, successfully commercialization of some 1,2,3-thiadiazoles such as tiadinil (TDL) and acibenzolar-S-methyl (BTH) as elicitors accelerated the studies on their synthesis and systemic acquired resistance (SAR).
In this thesis, five types of structures including altogether 128 (117 new compounds) 1,2,3-thiadiazole derivatives were designed and synthesized according to the principles of electronic isosteric, combination of bioactive sub-structure and combinatorial chemistry. All structures synthesized were characterized by IR, 1H NMR or 13C NMR, HRMS spectra or elemental analysis. Four typical crystals of each kind of the title compounds were chosen for culturation and determination of X-ray crystal diffraction for structural confirmation. The biological activities of the title compounds were also systematically determined. The contents and results of the studies are summarized as bellows:
In 1st part, 23 (12 new compounds) 4-methyl-1,2,3-thiadiazole-5- carboxylic acid aryl esters were designed and synthesized by using 4-methyl-1,2,3-thiadiazole-5- carbonyl chloride as an intermediate. The preliminary bioassay results indicated that the title compounds containing quinoline groups possessed a broad spectrum of fungicide activity with EC50 value ranged from 2.99 to 28.35μg/mL; some compounds exhibid good systemic acquired resistance for tobacco against tobacco mosaic virus (TMV) too. The results established basis for development of novel 1,2,3-thiadiazole lead with both fungicide activity and systemic acquired resistance.
In 2nd part, twenty-three new N-(4-methyl-1,2,3-thiadiazol-5-yl)-N′- heterocyclic ureas were designed and synthesized by using 4-methyl-1,2,3-thiadiazole- 5-carbonyl chloride as an intermediate. Bioassay results indicated that only compoundⅡ-18 had moderate post-emergence herbicidal activity; most of the title compounds only presented good fungicide activity against Sclerotinia sclerotiorum at 50μg/mL.
In the 3rd part, thirty-three novel N-[5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4- thiadiazol-2-yl] substituted amides were designed and synthesized according to the principle of combination of bioactive substructure using ethyl 4-methyl-1,2,3- thiadiazole-5-carboxylate as an intermediate. Bioassay results indicated that some title compounds had good fungicide activity at 50μg/mLand excellent insecticidal activity against Plutella xylostella L. at 400μg/mLand excellent larvicidal activity against Culex pipiens pallens at 5μg/mL.
In 4th part, two series including altogether thirty-eight novel 3,5-dichloro-4-(1,1, 2,2-tetrafluoroethoxy) phenyl containing 4-methyl-1,2,3-thiadiazoles were designed and synthesized via Ugi reaction by 4-methyl-1,2,3-thiadiazole-5-carboxylic acid as an intermediate. Bioassay results indicated that some title compounds had good fungicide activity and insecticidal activity, most of the compounds presented a certain degree of direct inhibition activity, good inactivation and curative activity against TMV at 500μg/mLand 100μg/mL, fluorine improved the activity of the title compounds.
The results of these studies indicated that 1,2,3-thiadiazole compounds exhibited various biological activities, and development of novel 1,2,3-thiadiazole lead with both fungicide and systemic acquired resistance had basis in theoretics and practice.
引文
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