CN103588727A - 2-巯基-1,3,4-噻二唑衍生物及其制备方法和用途 - Google Patents
2-巯基-1,3,4-噻二唑衍生物及其制备方法和用途 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- JLAMDELLBBZOOX-UHFFFAOYSA-N 3h-1,3,4-thiadiazole-2-thione Chemical class SC1=NN=CS1 JLAMDELLBBZOOX-UHFFFAOYSA-N 0.000 title abstract description 5
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- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 6
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical class O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDGIVSREGUOIJZ-UHFFFAOYSA-N 5-amino-3h-1,3,4-thiadiazole-2-thione Chemical compound NC1=NN=C(S)S1 GDGIVSREGUOIJZ-UHFFFAOYSA-N 0.000 claims abstract 2
- 150000002500 ions Chemical class 0.000 claims description 36
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
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- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
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- 229940006461 iodide ion Drugs 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
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- 238000012216 screening Methods 0.000 abstract description 2
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- 239000000243 solution Substances 0.000 description 31
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 19
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- 244000063299 Bacillus subtilis Species 0.000 description 8
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 238000000862 absorption spectrum Methods 0.000 description 7
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- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 4
- ITCMXBVIXVDAKR-UHFFFAOYSA-M azanium tetrabutylazanium diacetate Chemical compound C(C)(=O)[O-].[NH4+].C(CCC)[N+](CCCC)(CCCC)CCCC.C(C)(=O)[O-] ITCMXBVIXVDAKR-UHFFFAOYSA-M 0.000 description 4
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- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 4
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
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- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
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- NVKJOXRVEKMMHS-UHFFFAOYSA-N 5-nitro-1,2,4-triazol-3-one Chemical compound [O-][N+](=O)C1=NC(=O)N=N1 NVKJOXRVEKMMHS-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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Abstract
本发明公开了一类具有通式Ⅰ的噻唑衍生物及其制备方法和用途。其方法是将间位取代苯二醛与2-巯基-5-氨基-1,3,4-噻二唑在乙醇中反应得到具有通式Ⅰ的化合物。制备的2-巯基-1,3,4-噻二唑衍生物既具有广谱的抗菌活性又能选择性识别磷酸二氢根离子，为先导化合物的筛选提供重要依据，对生物、环境和药物等样品中磷酸二氢根离子的定量检测具有应用价值。
Description
技术领域
本发明涉及化学合成、分子识别和生物活性领域，具体涉及2-巯基-1,3,4-噻二唑衍生物的制备方法，本发明还公开了该噻二唑衍生物在阴离子检测和抗菌活性方面的用途。
背景技术
众所周知，噻二唑类衍生物是一类重要的杂环化合物，具有抗癌、抗菌、抗真菌等多种生物活性。特别是1,3,4-噻二唑衍生物的“碳氮硫”结构能作为活性中心螯合生物体内的某些金属离子，具有较好的细胞组织通透性。而且将不同骨架的杂环引入到噻二唑母核上，会对其生物活性产生影响。因此，近年来对具有新颖结构噻二唑类化合物的合成已成为有机合成的热点之一。阴离子广泛存在于生物体中，在医学、催化领域和环境科学中也有着举足轻重的作用。设计和合成生物学、医学和环境中重要阴离子的识别受体分子是当前超分子化学中迅速发展的研究领域之一，如酰胺、脲、硫脲、吡咯、酚羟基等氢键供体作为识别点，已被广泛应用于阴离子受体的设计和合成中。巯基也可作为氢键供体，但目前还未见文献报道以巯基作为识别位点的阴离子识别受体的合成。
发明内容
本发明提供一种2-巯基-1,3,4-噻二唑衍生物及其制备方法和用途。本发明将苯环和2-巯基-1,3,4-噻二唑耦合，合成了结构新颖的噻二唑类衍生物，使其具有抗菌活性和阴离子识别特性的双重功能，可为先导化合物的筛选提供重要依据，同时也拓宽了阴离子识别位点的研究领域，对阴离子识别的发展具有重要意义。
本发明的技术方案是：提供2-巯基-1,3,4-噻二唑衍生物，其结构如下式所示：
其中R是H、Br、Cl或NO2。
所述的化合物，其选自：N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-1,3-二亚甲胺基苯；或N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯。
本发明的另一目的在于，提供上述化合物的制备方法，包括：
其中R是H、Br、Cl或NO2。
所述的制备方法通过含有不同取代基的苯二醛与2-巯基-5-氨基-1,3,4-噻二唑在无水乙醇中加热回流反应10-12小时得到化合物Ⅰ，其中含有不同取代基的苯二醛与2-巯基-5-氨基-1,3,4-噻二唑的投料摩尔比为1：2～2.5。
本发明还提供了通式I化合物用于识别阴离子的用途。经分析测试，化合物Ⅰ具有结合阴离子的能力和广谱的抗菌活性。采用紫外－可见吸收光谱法、荧光发射光谱法和核磁共振氢谱方法测试了其对醋酸根离子、磷酸二氢根离子、氟离子、氯离子、溴离子及碘离子的选择性识别特性。采用琼脂扩散法研究了其对大肠杆菌、金黄色葡萄球菌、白色葡萄球菌、痢疾杆菌和枯草杆菌的抗菌活性。
进一步的，所述的阴离子是氟离子、氯离子、溴离子、碘离子、醋酸根离子或磷酸二氢根离子。
上述阴离子识别用途中，所述化合物Ⅰ是通过其结构中的巯基与磷酸二氢根阴离子发生相互作用的。
本发明进一步提供了通式I化合物作为对磷酸二氢根离子的一种检测工具的应用。
本发明还提供了通式I化合物的抗菌用途。其中，化合物Ⅰ对大肠杆菌、金黄色葡萄球菌、白色葡萄球菌或痢疾杆菌的抑制效果显著。
本发明选择以2-巯基-5-氨基-1,3,4-噻二唑为原料，设计、合成了一系列含有苯环的噻二唑衍生物。经初步试验显示，本发明化合物能结合阴离子，在所研究的阴离子中，对磷酸二氢根阴离子的结合能力最强，伴随明显的荧光响应，对生物、环境和药物等样品中磷酸二氢根阴离子的定量检测具有潜在应用价值。此外，本发明化合物还具有广谱的抗菌活性，其中对大肠杆菌、金黄色葡萄球菌、白色葡萄球菌和痢疾杆菌的抑制效果较好，对枯草杆菌的抑制效果较差。
采用紫外－可见吸收光谱法、荧光发射光谱法和核磁共振氢谱方法测试了其对醋酸根离子、磷酸二氢根离子、氟离子、氯离子、溴离子及碘离子的选择性识别特性。采用琼脂扩散法研究了其对大肠杆菌、金黄色葡萄球菌、白色葡萄球菌、痢疾杆菌和枯草杆菌的抗菌活性。
（1）阴离子键合能力：
紫外－可见吸收光谱法：将本发明所合成的化合物Ⅰ即主体均配成1×10－3mol/L的二甲基亚砜溶液，阴离子四丁基铵盐分别是四丁基氟化铵、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基醋酸铵、四丁基磷酸二氢铵均配成2×10－3mol/L的二甲基亚砜溶液。分别移取0.2mL主体溶液于一系列5mL比色管中，每支比色管中加入一定体积的阴离子的四丁基铵盐溶液，然后用二甲基亚砜溶剂稀释至刻度，得到一系列化合物浓度恒定、阴离子浓度不同的溶液，混合均匀后测其吸收光谱，二甲基亚砜溶剂作参比。根据最大吸收波长处的吸光度值经非线性最小二乘法曲线拟合计算可得到化合物Ⅰ与不同阴离子作用的结合常数。结果表明：在所研究的阴离子中，化合物Ⅰ对H2PO4 －的结合能力最强，对CH3COO－和F－存在不同程度的结合，对Cl－、Br－、I－的结合能力较弱。
荧光发射光谱法：将本发明所合成的化合物即主体均配成1×10－3mol/L的二甲基亚砜溶液，阴离子四丁基铵盐分别是四丁基氟化铵、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基醋酸铵、四丁基磷酸二氢铵均配成2×10－3mol/L的二甲基亚砜溶液。分别移取0.2mL主体溶液于一系列5mL比色管中，每支比色管中加入一定体积的阴离子的四丁基铵盐溶液，然后用二甲基亚砜稀释至刻度，得到一系列化合物浓度恒定、阴离子浓度不同的溶液，混合均匀后测其荧光发射光谱，二甲基亚砜溶剂作参比。根据最大发射峰处的强度值经非线性最小二乘法曲线拟合计算可得到化合物Ⅰ与不同阴离子作用的结合常数。结果表明：在所研究的阴离子中，化合物Ⅰ对H2PO4 －的结合能力最强，对CH3COO－和F－存在不同程度的结合，对Cl－、Br－、I－的结合能力较弱。上述结果与紫外-可见吸收光谱结果一致。
核磁方法：将本发明所合成的化合物和四丁基铵盐的阴离子配成0.1mol/L的DMSO-d6溶液，分别移取50μL主体溶液注入5支核磁管中，依次加入0、25、50、75和100μL的阴离子的DMSO-d6溶液。然后加DMSO-d6溶剂定容至0.5mL。测试结果表明：主体是通过巯基上的氢和阴离子形成氢键作用的。
（2）抗菌活性：
抗菌活性实验采用琼脂扩散法进行，在无菌条件下，将受试菌种（大肠杆菌、金黄色葡萄球菌、白色葡萄球菌、痢疾杆菌和枯草杆菌）接种到斜面培养基上，37℃活化两次，再接种到适量营养肉汤中，培养24h后备用。采用10倍稀释法将原菌液稀释到107个/mL备用。所有化合物用适量的二甲基亚砜溶解，加水稀释配成0.5g/L溶液，二甲基亚砜/水溶剂系统做空白试验，用稀释平板法测定抑菌效果。结果表明：化合物Ⅰ具有广谱的抗菌活性，其中对大肠杆菌、金黄色葡萄球菌、白色葡萄球菌和痢疾杆菌的抑制效果较好，对枯草杆菌的抑制效果较差。
本发明合成路线合理可行，步骤简单，条件温和，收率较高，对磷酸二氢根阴离子的结合能力较强，且具有广谱的抗菌活性。
具体实施方式
本发明突出的实质性的特点和积极效果可以从下述实施例中得以体现，但是它们并不是对本发明作任何限制。
实施例1
N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯的合成
2-巯基-5-氨基-1,3,4-噻二唑(2mmol,266mg)溶于无水乙醇中(20mL)，磁搅拌下加入3滴冰醋酸，5-硝基-1,3-苯二甲醛(1mmol,179mg)逐滴加入到上述溶液中。在氮气氛围中，混合液加热回流反应12h。反应完毕冷却、抽滤得到黄色目标物，经无水乙醇重结晶、乙醚洗涤、真空干燥得黄色固体。产率：87%。1H NMR(400MHz,DMSO-d6,298K)δ13.17(s,2H,SH),10.64(s,2H,CH),7.09(s,3H,ph-H)。元素分析：计算值C12H7N7O2S4:C,35.20;H,1.72;N,23.94;实验值：C,35.51;H,1.29;N,24.18。ESI-MS(m/z):407.8(M-H)-。
实施例2
紫外－可见吸收光谱实验
将本发明合成的化合物N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯即主体配成1×10-3mol/L的二甲基亚砜溶液，阴离子四丁基铵盐分别是四丁基氟化铵、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基醋酸铵、四丁基磷酸二氢铵均配成2×10-3mol/L的二甲基亚砜溶液。移取0.2mL主体溶液于一系列5mL比色管中，每支比色管中加入一定体积的阴离子的四丁基铵盐溶液，然后用二甲基亚砜溶剂稀释至刻度，得到一系列主体浓度恒定、阴离子浓度不同的溶液，混合均匀后测其吸收光谱，二甲基亚砜溶剂作参比。根据最大吸收峰处的强度值经非线性最小二乘法曲线拟合计算可得到该化合物与不同阴离子作用的结合常数，结果列于表1。
表1化合物与不同阴离子的结合常数
a所有阴离子都以四丁基铵盐的形式加入
bND：光谱响应较小，结合常数无法计算
实验结果表明：在所研究的阴离子中，N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯对H2PO4 -显示了最强的结合能力，对CH3COO-、F-显示了不同程度的结合能力，对Cl－、Br－、I－的键合能力较弱。
实施例3
荧光发射光谱实验
将本发明合成的化合物N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯即主体配成1×10-3mol/L的二甲基亚砜溶液，阴离子四丁基铵盐分别是四丁基氟化铵、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵、四丁基醋酸铵、四丁基磷酸二氢铵均配成2×10-3mol/L的二甲基亚砜溶液。移取0.2mL主体溶液于一系列5mL比色管中，每支比色管中加入一定体积的阴离子的四丁基铵盐溶液，然后用二甲基亚砜稀释至刻度，得到一系列化合物浓度恒定、阴离子浓度不同的溶液，混合均匀后测其荧光发射光谱，二甲基亚砜溶剂作参比。根据最大发射峰处的强度值经非线性最小二乘法曲线拟合计算可得到化合物Ⅰ与不同阴离子作用的结合常数，结果列于表2。
表2化合物与不同阴离子的结合常数
a所有阴离子都以四丁基铵盐的形式加入
bND：光谱响应较小，结合常数无法计算
实验结果表明：在所研究的阴离子中，N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯对H2PO4 -显示了最强的的结合能力，对CH3COO-、F-显示了不同程度的结合能力，对Cl－、Br－、I－的键合能力较弱，上述结论与紫外-可见光谱实验结果一致。另外，对于同种阴离子，荧光光谱所得结合常数数据与紫外-可见光谱的数据在同一数量级，由此证实了所得结合常数的准确性。
实施例4
核磁滴定实验：
将本发明所合成的化合物N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯和四丁基铵盐的阴离子配成0.1mol/L的DMSO-d6溶液，分别移取50μL主体溶液注入5支核磁管中，依次加入0、25、50、75和100μL的阴离子的DMSO-d6溶液，然后加DMSO-d6溶液定容至0.5mL。测试结果表明：主体是通过巯基上的氢和阴离子形成氢键作用的。
实施例5
抗菌活性：
抗菌活性实验采用琼脂扩散法进行，在无菌条件下，将受试菌种（大肠杆菌、金黄色葡萄球菌、白色葡萄球菌、痢疾杆菌和枯草杆菌）接种到斜面培养基上，37℃活化两次，再接种到适量营养肉汤中，培养24h后备用。采用10倍稀释法将原菌液稀释到107个/mL备用。化合物N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯溶于适量的二甲基亚砜溶剂中，加水稀释配成0.5g/L溶液，二甲基亚砜/水溶剂系统做空白试验，用稀释平板法测定抑菌效果（如表3所示）。结果表明：化合物N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯具有广谱的抗菌活性，其中对大肠杆菌、金黄色葡萄球菌、白色葡萄球菌和痢疾杆菌的抑制效果较好，对枯草杆菌的抑制效果较差。
表3抑菌实验(n=8)
与枯草杆菌比较：**P<0.01
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.2-巯基-1,3,4-噻二唑衍生物，其结构如下式所示：
其中R是H、Br、Cl或NO2。
2.根据权利权利要求1所述的化合物，其特征在于，其选自：
N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-1,3-二亚甲胺基苯；或
N,N’-二((2’-巯基-1’,3’,4’-噻二唑)-5’)-5-硝基-1,3-二亚甲胺基苯。
3.权利要求1所述化合物的制备方法，其特征在于，包括：
其中R是H、Br、Cl或NO2。
4.根据权利要求3的制备方法，其特征在于，含有不同取代基的苯二醛与2-巯基-5-氨基-1,3,4-噻二唑在无水乙醇中加热回流反应10-12小时得到化合物Ⅰ，含有不同取代基的苯二醛与2-巯基-5-氨基-1,3,4-噻二唑的投料摩尔比为1：2～2.5。
5.权利要求1所述的通式I化合物用于识别阴离子的用途。
6.根据权利要求5所述的用途，其特征在于，所述的阴离子是氟离子、氯离子、溴离子、碘离子、醋酸根离子或磷酸二氢根离子。
7.根据权利要求5所述的用途，其特征在于，化合物Ⅰ是通过其结构中的巯基与磷酸二氢根阴离子发生相互作用的。
8.权利要求1所述的通式I化合物作为对磷酸二氢根离子的一种检测工具。
9.权利要求1所述的通式I化合物的抗菌用途。
10.根据权利要求9所述的通式I化合物的抗菌用途，其特征在于，化合物Ⅰ用于抑制大肠杆菌、金黄色葡萄球菌、白色葡萄球菌或痢疾杆菌。
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| CN103969429B (zh) * | 2014-05-28 | 2016-02-03 | 甘肃农业大学 | N-5(2-巯基-1,3,4-噻二唑)对苯二亚胺在检测氰根离子、铜离子中的应用 |
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