methyl 5-isopropyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylate | 566946-82-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: methyl 5-isopropyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylate
• 英文别名: methyl 2-(1-methyl-4-nitro-1H-pyrrole-2-carboxamido)-5-isopropylthiazole-4-carboxylate；methyl 2-[(1-methyl-4-nitropyrrole-2-carbonyl)amino]-5-propan-2-yl-1,3-thiazole-4-carboxylate
• CAS: 566946-82-5
• 化学式: C₁₄H₁₆N₄O₅S
• 分子量: 352.371
• InChiKey: JFJFFSZWIKPYLG-UHFFFAOYSA-N

物化性质

• 熔点：
  118-120 °C
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  147
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 5-isopropyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylate 在 palladium 10% on activated carbon 、 水 、 氢气 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 、 lithium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 48.0h， 生成 2-[[4-[(4-amino-1-methyl-pyrrole-2-carbonyl)amino]-1-methyl-pyrrole-2-carbonyl]amino]-5-isopropyl-N-(2-morpholinoethyl)thiazole-4-carboxamide
  参考文献：
  名称：

  An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics

  摘要：

  A series of 32, structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activity. (C) 2016 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.orgilicensesiby/4.0/).

  DOI：

  10.1016/j.ejmech.2016.03.064
• 作为产物：
  描述：

  1-甲基-4-硝基吡咯-2-羧酸 在 氯化亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 生成 methyl 5-isopropyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylate
  参考文献：
  名称：

  小沟粘合剂作为抗肺癌治疗剂的评估

  摘要：

  通过针对黑素瘤癌细胞系B16-F10进行筛选，评估了一系列47种结构多样的MGB（源自天然产物双歧霉素）的抗肺癌活性。已经发现有五种化合物具有显着的活性，比标准疗法吉西他滨具有更多的活性。此外，已发现一种化合物的活性约为吉西他滨的70倍，且选择性指数大于125。此外，初步研究表明该化合物具有代谢稳定性，因此代表了进一步优化的先导寻求一种新型的肺癌治疗方法。

  DOI：

  10.1016/j.bmcl.2016.06.040

文献信息

• Synthesis and antimicrobial activity of some netropsin analogues
  作者：Abedawn I. Khalaf、Abdolrasoul H. Ebrahimabadi、Allan J. Drummond、Nahoum G. Anthony、Simon P. Mackay、Colin J. Suckling、Roger D. Waigh

  DOI：10.1039/b408386p

  日期：——

  Nine novel lexitropsins were synthesized by linking two netropsin-like moieties through three different dicarboxylic acids; 9,10-dihydro-2,7-phenanthrenedicarboxylic acid; [(3-[(carboxymethyl)amino]carbonyl}benzoyl)amino]acetic acid and indole-2,5-dicarboxylic acid. The netropsin residues were modified by the use of N-isopentylpyrrole, 5-methylthiophene or 5-isopropylthiazole heterocyclic building blocks in place of the usual N-methylpyrrole. The compounds were tested against five gram-positive bacteria: Staphylococcus aureus, Streptomyces faecalis, methicillin resistant Staphylococcus aureus, Enterobacter cloacae, Mycobacterium fortuitum, three gram-negative bacteria: Klebsiella aerogenes, Proteus vulgaris, Escherichia coli and three fungi: Aspergillus niger, Candida albicans and Aspergillus nidulans. Some of the compounds showed significant inhibitory effects on the growth of the microorganisms.

  合成了九种新型lexitropsin，通过三种不同的二羧酸（9,10-二氢-2,7-菲二羧酸；[(3-[(羧甲基)氨基]羰基}苯甲酰)氨基]乙酸和吲哚-2,5-二羧酸）将两个类似netropsin的部分连接在一起。通过使用N-异戊基吡咯、5-甲基噻吩或5-异丙基噻唑异构体构建单元替代通常的N-甲基吡咯，对netropsin残基进行修饰。将这些化合物分别针对五种革兰阳性菌：金黄色葡萄球菌、肠球菌、耐甲氧西林金黄色葡萄球菌、克雷伯氏菌和偶然分枝杆菌，三种革兰阴性菌：气单胞菌、变形杆菌、大肠杆菌，以及三种真菌：黑曲霉、白念珠菌和安氏曲霉进行了测试。其中一些化合物对微生物的生长表现出显著的抑制作用。
• Distamycin Analogues with Enhanced Lipophilicity:  Synthesis and Antimicrobial Activity
  作者：Abedawn I. Khalaf、Roger D. Waigh、Allan J. Drummond、Breffni Pringle、Ian McGroarty、Graham G. Skellern、Colin J. Suckling

  DOI：10.1021/jm031089x

  日期：2004.4.1

  Forty-eight heterocyclic amino acid trimers, analogues of distamycin, with a number of features that enhance lipophilicity are described. They contain alkyl or cycloalkyl groups larger than methyl; some are N-terminated by acetamide or methoxybenzamide and are C-terminated by dimethylaminopropyl or aliphatic heterocylic aminopropyl substituents. The ability of these compounds to bind principally to

  描述了四十八个杂环氨基酸三聚体，它是二霉素的类似物，具有许多增强亲脂性的特征。它们含有比甲基大的烷基或环烷基；一些被乙酰胺或甲氧基苯甲酰胺N端基，并且被二甲氨基丙基或脂族杂环甲基氨基丙基取代基C端基。使用毛细管区带电泳已经评估了这些化合物主要结合至DNA AT束的能力。几种化合物，特别是那些含有噻唑的化合物，显示出对关键生物如MRSA和白色念珠菌的显着抗菌活性。而且，这些化合物对几种哺乳动物细胞系具有低毒性。
• Novel distamycin analogues that block the cell cycle of African trypanosomes with high selectivity and potency
  作者：Jaime Franco、Laura Scarone、Marcelo A. Comini

  DOI：10.1016/j.ejmech.2020.112043

  日期：2020.3

  have been reported to halt the proliferation of deadly African trypanosomes by different and unrelated mechanisms. Here we describe the synthesis and preliminary characterization of the anti-trypanosomal mode of action of new potent and selective distamycin analogues. Two tri-heterocyclic derivatives containing a central N-methyl pyrrole ring (16 and 17) displayed high activity (EC50 < 20 nM) and selectivity

  与链霉菌双歧霉素和netropsin相关的基于聚酰胺的化合物是有效的细胞抑制分子，可与DNA小沟的AT富集区域结合，从而干扰DNA复制和转录。最近，据报道，属于该支架的衍生物通过不同且无关的机制阻止了致命的非洲锥虫的增殖。在这里，我们描述了新的强效和选择性双歧霉素类似物的抗锥虫作用模式的合成和初步表征。含有一个中心N-甲基吡咯环（16和17）的两个三杂环衍生物对布鲁氏杆菌的感染形式表现出高活性（EC50 <20 nM）和选择性（相对于哺乳动物巨噬细胞而言，选择性指数> 5000）。两种化合物均通过阻断线粒体DNA的复制而导致细胞周期停滞，但不影响其完整性。这种作用方式明显不同于传统的小沟结合剂（MGB）药物，后者诱导线粒体DNA降解。与此相符，体外试验表明16和17对不同模板DNA的亲和力比MGB药物地那敏低。治疗功效研究和稳定性测定表明，应优化命中的药理特性。这些化合物可被视为设计高效和
• Dna minor groove binding compounds
  申请人：Khalaf Abedawn

  公开号：US20070117760A1

  公开（公告）日：2007-05-24

  There is provided an oligopeptide compound comprising: (a) at least one nitrogen-containing basic group attached to at least one end of the oligopeptide; and (b) two or more heterocyclic monomers, at least one of which is substituted in the heterocyclic part by a branched, cyclic or part cyclic C 3-5 alkyl group, or a pharmaceutically acceptable salt or solvate thereof; which compound, salt or solvate binds to the minor groove of DNA.

  提供一种寡肽化合物，包括：（a）至少一个含氮的碱性基团连接到寡肽的至少一个末端；以及（b）两个或更多的杂环单体，其中至少一个在杂环部分被支链、环状或部分环状的C3-5烷基取代，或其药学上可接受的盐或溶剂；该化合物、盐或溶剂与DNA的小沟结合。
• Synthesis and Evaluation of Novel DNA Minor Groove Binders as Antiamoebic Agents
  作者：Hasan Y. Alniss、Naveed A. Khan、Anania Boghossian、Noor Akbar、Hadeel M. Al-Jubeh、Yousef A. Msallam、Balsam Q. Saeed、Ruqaiyyah Siddiqui

  DOI：10.3390/antibiotics11070935

  日期：——

  The free-living amoeba Acanthamoeba castellanii is responsible for the central nervous infection granulomatous amoebic encephalitis and sight-threatening infection Acanthamoeba keratitis. Moreover, no effective treatment is currently present, and a combination drug therapy is used. In this study, twelve DNA minor groove binders (MGBs) were synthesized and tested for their antiamoebic activity via amoebicidal, encystation, excystation, and cytopathogenicity assays. It was found that the compounds MGB3, MGB6, MGB22, MGB24, and MGB16 significantly reduce amoeba viability to 76.20%, 59.45%, 66.5%, 39.32%, and 43.21%, respectively, in amoebicidal assays. Moreover, the compounds MGB6, MGB20, MGB22, MGB28, MGB30, MGB32, and MGB16 significantly inhibit Acanthamoeba cysts, leading to the development of only 46.3%, 39%, 30.3%, 29.6%, 27.8%, 41.5%, and 45.6% cysts. Additionally, the compounds MGB3, MGB4, MGB6, MGB22, MGB24, MGB28, MGB32, and MGB16 significantly reduce the re-emergence of cysts to trophozoites, with viable trophozoites being only 64.3%, 47.3%, 41.4%, 52.9%, 55.4%, 40.6%, 62.1%, and 51.7%. Moreover, the compounds MGB3, MGB4, and MGB6 exhibited the greatest reduction in amoeba-mediated host-cell death, with cell death reduced to 41.5%, 49.4%, and 49.5%. With the following determined, future in vivo studies can be carried out to understand the effect of the compounds on animal models such as mice.

  自由生活的阿米巴原虫 Acanthamoeba castellanii 是造成中枢神经感染肉芽肿阿米巴脑炎和危及视力感染 Acanthamoeba 角膜炎的罪魁祸首。此外，目前还没有有效的治疗方法，只能采用联合药物治疗。本研究合成了 12 种 DNA 小沟结合剂（MGBs），并通过阿米巴杀灭试验、阿米巴囊肿形成试验、阿米巴外囊形成试验和细胞致病性试验测试其抗阿米巴活性。结果发现，在杀阿米巴试验中，化合物 MGB3、MGB6、MGB22、MGB24 和 MGB16 能显著降低阿米巴的存活率，分别为 76.20%、59.45%、66.5%、39.32% 和 43.21%。此外，化合物 MGB6、MGB20、MGB22、MGB28、MGB30、MGB32 和 MGB16 还能显著抑制阿卡阿米巴囊肿，使囊肿发育率分别降至 46.3%、39%、30.3%、29.6%、27.8%、41.5% 和 45.6%。此外，化合物 MGB3、MGB4、MGB6、MGB22、MGB24、MGB28、MGB32 和 MGB16 还能显著减少包囊向滋养体的再萌发，有活力的滋养体只占 64.3%、47.3%、41.4%、52.9%、55.4%、40.6%、62.1% 和 51.7%。此外，MGB3、MGB4 和 MGB6 化合物对阿米巴介导的宿主细胞死亡的降低幅度最大，分别降低了 41.5%、49.4% 和 49.5%。有了以下确定的结果，今后就可以开展体内研究，以了解化合物对小鼠等动物模型的影响。