4-phenylpiperazine-1-carbothiohydrazide | 683224-24-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-phenylpiperazine-1-carbothiohydrazide
• 英文别名: 4-Phenylpiperazinecarbothioic acid hydrazide
• CAS: 683224-24-0
• 化学式: C₁₁H₁₆N₄S
• 分子量: 236.341
• InChiKey: VRTTXYSIYUPMIW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  76.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-phenylpiperazine-1-carbothiohydrazide 在 氢氧化钾 作用下， 以 乙醇 、 二甲基亚砜 为溶剂， 反应 0.8h， 生成 5-(4-phenylpiperazin-1-yl)-[1,3,4]thiadiazol-2-thiol
  参考文献：
  名称：

  Synthesis and Antibacterial Activity of Substituted Thiosemicarbazides and of 1,3,4-Thiadiazole or 1,2,4-Triazole Derivatives

  摘要：

  The synthesized series of new thiosemicarbazide derivatives (1, 6-10) in reactions with carbon disulphide produced, according to the reaction conditions, the dithioacids (4, 30) or the 5-substituted 1,3,4-thiadiazolo-2-thiol derivatives (2, 27). The dithioacids were cyclized, in the reaction with hydrazine, into the 4ami-no-1,2,4-triazolo-2-thiol derivatives (5, 31). One of these compounds (31) was transformed into the 1,2,4-triazolo-1,3,4-thiadiazine derivative (33). The compounds 6-9 were also exposed to the condensation with aldehydes. 4-phenylpiperazinocarbothiohydrazide (6) was exposed to the action of isothiocyanates, which gave the compounds 16-20, and these cyclized to the 1,3,4-thiadiazoloamino derivatives (21-23).The susceptibility of aerobic and anaerobic bacteria to some of the new derivatives were tested. The anaerobes were the most susceptible at concentrations in ranges less than 6.2 to 100 mu g/mL to derivative: 9 (64% were susceptible), 1, 13 (for 60%), and 7 (for 56%).

  DOI：

  10.1080/10426500500269851
• 作为产物：
  描述：

  4-N(phenyl)piperazino dithiocarbamate 在 一水合肼 作用下， 以 乙醇 、 水 为溶剂， 反应 17.0h， 生成 4-phenylpiperazine-1-carbothiohydrazide
  参考文献：
  名称：

  Synthesis and Antibacterial Activity of Substituted Thiosemicarbazides and of 1,3,4-Thiadiazole or 1,2,4-Triazole Derivatives

  摘要：

  The synthesized series of new thiosemicarbazide derivatives (1, 6-10) in reactions with carbon disulphide produced, according to the reaction conditions, the dithioacids (4, 30) or the 5-substituted 1,3,4-thiadiazolo-2-thiol derivatives (2, 27). The dithioacids were cyclized, in the reaction with hydrazine, into the 4ami-no-1,2,4-triazolo-2-thiol derivatives (5, 31). One of these compounds (31) was transformed into the 1,2,4-triazolo-1,3,4-thiadiazine derivative (33). The compounds 6-9 were also exposed to the condensation with aldehydes. 4-phenylpiperazinocarbothiohydrazide (6) was exposed to the action of isothiocyanates, which gave the compounds 16-20, and these cyclized to the 1,3,4-thiadiazoloamino derivatives (21-23).The susceptibility of aerobic and anaerobic bacteria to some of the new derivatives were tested. The anaerobes were the most susceptible at concentrations in ranges less than 6.2 to 100 mu g/mL to derivative: 9 (64% were susceptible), 1, 13 (for 60%), and 7 (for 56%).

  DOI：

  10.1080/10426500500269851

文献信息

• Piperazinyl fragment improves anticancer activity of Triapine
  作者：Marta Rejmund、Anna Mrozek-Wilczkiewicz、Katarzyna Malarz、Monika Pyrkosz-Bulska、Kamila Gajcy、Mieczyslaw Sajewicz、Robert Musiol、Jaroslaw Polanski

  DOI：10.1371/journal.pone.0188767

  日期：——

  A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial prerequisite for the high activity of the previously obtained TSC compounds–DpC and Dp44mT. We tested the important physicochemical characteristics of the novel compounds L1-L12. The studied ligands are neutral at physiological pH, which allows them to permeate cell membranes and bind cellular Fe pools more readily than less lipid-soluble ligands, e.g. DFO. The selectivity and anti-cancer activity of the novel TSCs were examined in a variety of cancer cell types. In general, the novel compounds demonstrated the greatest promise as anti-cancer agents with both a potent and selective anti-proliferative activity. We investigated the mechanism of action more deeply, and revealed that studied compounds inhibit the cell cycle (G1/S phase). Additionally we detected apoptosis, which is dependent on cell line’s specific genetic profile. Accordingly, structure-activity relationship studies suggest that the combination of the piperazine ring with Triapine allows potent and selective anticancer chelators that warrant further in vivo examination to be identified. Significantly, this study proved the importance of the di-substitution pattern of the amine N4 function.

  设计了一类包含哌嗪的Triapine（哌嗪类似物）作为靶向铁硫簇（TSCs）的新一类化合物，旨在实现TSCs的N4位置上的二取代模式，这是先前获得的具有高活性的TSC化合物–DpC和Dp44mT的关键前提。我们测试了新型化合物L1-L12的重要物理化学特性。这些配体在生理pH下呈中性，这使得它们比亲脂性较低的配体（如DFO）更容易穿透细胞膜并结合细胞内的铁库。在多种癌细胞类型中检测了这些新型TSCs的选择性和抗癌活性。总体而言，这些新型化合物展现出最有希望作为抗癌剂，具有强效且选择性的抗增殖活性。我们更深入地研究了这些化合物的作用机制，发现它们能够抑制细胞周期（G1/S期）。此外，我们还检测到了依赖于细胞系特定遗传背景的凋亡现象。因此，构效关系研究表明，哌嗪环与Triapine的结合使得能够识别出具有强效且选择性的抗癌螯合剂，这些螯合剂值得进一步进行体内研究。值得注意的是，这项研究证明了胺N4功能的二取代模式的重要性。
• The synthesis and tuberculostatic activity of benzenesulfonohydrazide derivatives
  作者：Krystyna Wisterowicz、Katarzyna Gobis、Henryk Foks、Ewa Augustynowicz-Kopeć

  DOI：10.1002/hc.20743

  日期：——

  chlorides with various aminocarbothiohydrazides. The structures were confirmed by IR and NMR spectra as well as elemental analysis. All of the obtained compounds were screened in vitro for their tuberculostatic activity. Preliminary results indicated that some target compounds exhibited promising results, especially toward Mycobacterium tuberculosis (Mtb) resistant strain 210. © 2011 Wiley Periodicals

  通过苯磺酰氯与各种氨基碳硫酰肼反应合成了一系列新型N'-氨基碳硫酰-苯磺酰肼。结构经红外光谱和核磁共振光谱以及元素分析证实。对所有获得的化合物进行体外抗结核活性筛选。初步结果表明，一些目标化合物表现出有希望的结果，尤其是对结核分枝杆菌 (Mtb) 耐药菌株 210。 © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:99–104, 2012；在 wileyonlinelibrary.com 上在线查看这篇文章。DOI 10.1002/hc.20743
• Synthesis, structure and biological activity of four new picolinohydrazonamide derivatives
  作者：Małgorzata Szczesio、Katarzyna Gobis、Izabela Korona-Głowniak、Ida Mazerant-Politowicz、Dagmara Ziembicka、Henryk Foks、Marek Główka、Andrzej Olczak

  DOI：10.1107/s2053229620007822

  日期：2020.7.1

  Four new picolinohydrazonamide derivatives, namely, 6-methyl-N′-(morpholine-4-carbonothioyl)picolinohydrazonamide, C₁₂H₁₇N₅OS, 6-chloro-N′-(morpholine-4-carbonothioyl)picolinohydrazonamide methanol monosolvate, C₁₁H₁₄ClN₅OS·CH₃OH, 6-chloro-N′-(4-phenylpiperazine-1-carbonothioyl)picolinohydrazonamide, C₁₇H₁₉ClN₆S, and 6-chloropicolinohydrazonamide, C₆H₇ClN₄, have been synthesized and characterized by NMR spectroscopy and single-crystal low-temperature X-ray diffraction. In addition, their antibacterial and anti-yeast activities have been determined. The first three compounds adopt the zwitterionic form in the crystal structure regardless of the presence or absence of solvent molecules in the structure. They also adopt the same symmetry, i.e. P2₁/c (P2₁/n), unlike the fourth structure which is chiral and has the space group P2₁2₁2₁. For all the studied cases, intermolecular N—H...O and N—H...N hydrogen bonds play an essential role in the formation of the structures.

  四种新的吡啶甲酰肼衍生物，即 6-甲基-N′-(吗啉-4-甲硫基)吡啶甲酰肼，C12H17N5OS；6-氯-N′-(吗啉-4-甲硫基)吡啶甲酰肼甲醇单溶酯，C11H14ClN5OS-CH3OH、合成了 6-氯-N′-(4-苯基哌嗪-1-碳硫酰基)吡啶甲酰肼（C17H19ClN6S）和 6-氯-吡啶甲酰肼（C6H7ClN4），并通过核磁共振光谱和单晶低温 X 射线衍射进行了表征。此外，还测定了它们的抗菌和抗酵母活性。无论晶体结构中是否存在溶剂分子，前三种化合物在晶体结构中都采用了齐聚物形式。它们还采用了相同的对称性，即 P21/c（P21/n），而第四种结构则不同，它是手性结构，空间群为 P212121。在所研究的所有结构中，分子间的 N-H...O 和 N-H...N 氢键在结构的形成过程中起着至关重要的作用。
• Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships
  作者：Maciej Serda、Danuta S. Kalinowski、Nathalie Rasko、Eliška Potůčková、Anna Mrozek-Wilczkiewicz、Robert Musiol、Jan G. Małecki、Mieczysław Sajewicz、Alicja Ratuszna、Angelika Muchowicz、Jakub Gołąb、Tomáš Šimůnek、Des R. Richardson、Jaroslaw Polanski

  DOI：10.1371/journal.pone.0110291

  日期：——

  Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination.

  硫代氨基脲（TSCs）是一类有趣的配体，具有多种生物活性，包括抗真菌、抗病毒和抗癌作用。我们之前的研究已经证明，新型 TSCs 具有强大的体内抗肿瘤活性，并能克服临床使用的化疗药物的抗药性。在目前的研究中，我们利用在其他 TSCs 中出现的逆片段组合设计了 6 个不同类别的 35 种新型 TSCs。此外，通过加入基于 N4 原子的哌嗪或吗啉环，保留了 N4 原子末端的二取代，这在以前的研究中被认为是强效抗癌活性的关键。研究人员在多种癌症和正常细胞类型中考察了新型 TSCs 的抗增殖活性。其中，化合物 1d 和 3c 最有希望成为具有强效和选择性抗增殖活性的抗癌剂。结构-活性关系研究表明，利用氮和硫等 "软 "供体原子的螯合剂具有很强的抗癌活性。事实上，N,N,S 供体原子组对形成具有氧化还原活性的铁络合物至关重要，这种络合物能够介导抗坏血酸的氧化。这进一步凸显了活性氧生成在介导强效抗癌活性方面的重要作用。值得注意的是，这项研究发现了 1d 和 3c 的强效选择性抗癌活性，值得进一步研究。
• 4-Substituted picolinohydrazonamides as a new class of potential antitubercular agents
  作者：Malwina Krause、Henryk Foks、Dagmara Ziembicka、Ewa Augustynowicz-Kopeć、Agnieszka Głogowska、Izabela Korona-Głowniak、Krzysztof Bojanowski、Danuta Siluk、Katarzyna Gobis

  DOI：10.1016/j.ejmech.2020.112106

  日期：2020.3

  The series of new 4-substituted picolinohydrazonamides were synthesized (6-25) and evaluated for tuberculostatic activity. Compounds having a hydrophilic cyclic amine such as morpholine and pyrrolidine at the end of the thiosemicarbazide chain, exhibited the highest antimycobacterial activity. The antimycobacterial activity of compounds 6, 11, and 15 (MIC 0.4-0.8 μg/mL) was higher than that of reference

  合成了一系列新的4-取代的吡咯并酰肼酰胺（6-25），并评估了其抑菌活性。在硫代氨基脲链的末端具有亲水环胺的化合物，例如吗啉和吡咯烷，表现出最高的抗分枝杆菌活性。化合物6、11和15（MIC 0.4-0.8μg/ mL）的抗分枝杆菌活性高于参考药物。此外，衍生物15表现出对其他测试微生物如革兰氏阳性，革兰氏阴性或真菌的较低活性。因此，该化合物的特征在于抗微生物活性的选择性。针对人类皮肤成纤维细胞（HDF）和小鼠黑素瘤细胞系（B16-F10）进行的抗增殖研究表明，化合物15的细胞毒性较低。