1-(4-chlorophenyl)-3-[(5-methyl-1H-imidazole-4-carbonyl)amino]thiourea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(4-chlorophenyl)-3-[(5-methyl-1H-imidazole-4-carbonyl)amino]thiourea
• 化学式: C₁₂H₁₂ClN₅OS
• 分子量: 309.779
• InChiKey: FQGZIGDTMBMIOD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  114
• 氢给体数：
  4
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(4-chlorophenyl)-3-[(5-methyl-1H-imidazole-4-carbonyl)amino]thiourea 在 sodium hydroxide 作用下， 反应 2.0h， 以74%的产率得到4-(4-chlorophenyl)-5-(4-methylimidazol-5-yl)-1,2,4-triazole-3-thione
  参考文献：
  名称：

  Inhibition of Toxoplasma gondii by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine

  摘要：

  DOI：

  10.1080/14756366.2022.2112576
• 作为产物：
  描述：

  4-氯异硫氰酸苯酯 、 (9ci)-5-甲基-1H-咪唑-4-羧酸肼 以 乙醇 为溶剂， 生成 1-(4-chlorophenyl)-3-[(5-methyl-1H-imidazole-4-carbonyl)amino]thiourea
  参考文献：
  名称：

  Imidazole-Thiosemicarbazide Derivatives as Potent Anti-Mycobacterium tuberculosis Compounds with Antibiofilm Activity

  摘要：

  结核分枝杆菌（Mtb）是一种细胞内病原菌，是结核病的病原体。这种疾病是最古老和最致命的细菌感染之一，因为它在全球范围内主要对低收入和中等收入国家构成了重大的健康、社会和经济挑战。缺乏有效的疫苗、长期昂贵的药物治疗和快速传播的耐药菌株导致结核病重新成为全球流行病。本研究评估了新的咪唑硫脲衍生物（ITDs）对Mtb感染的体外活性以及它们对分枝杆菌生物膜形成的影响。对新化合物在细胞系和人单核细胞源性巨噬细胞（MDMs）中的细胞毒性进行了研究。通过测定还原蓝的最小抑菌浓度、时间杀菌曲线、细菌细胞内生长和对生物膜形成的影响来评估ITDs的抗Mtb活性。进行了对ITDs耐药突变体的突变频率和全基因组测序。观察到具有穿透Mtb感染的人类巨噬细胞的能力、显著抑制结核杆菌细胞内生长和抑制Mtb生物膜形成的ITDs的抗分枝杆菌潜力。

  DOI：

  10.3390/cells10123476

文献信息

• Discovery of Potent and Selective Halogen-Substituted Imidazole-Thiosemicarbazides for Inhibition of Toxoplasma gondii Growth In Vitro via Structure-Based Design
  作者：Agata Paneth、Lidia Węglińska、Adrian Bekier、Edyta Stefaniszyn、Monika Wujec、Nazar Trotsko、Anna Hawrył、Miroslaw Hawrył、Katarzyna Dzitko

  DOI：10.3390/molecules24081618

  日期：——

  Employing a simple synthetic protocol, a series of highly effective halogen-substituted imidazole-thiosemicarbazides with anti-Toxoplasma gondii effects against the RH tachyzoites, much better than sulfadiazine, were obtained (IC50s 10.30—113.45 µg/mL vs. ~2721.45 µg/mL). The most potent of them, 12, 13, and 15, blocked the in vitro proliferation of T. gondii more potently than trimethoprim (IC50 12.13 µg/mL), as well. The results of lipophilicity studies collectively suggest that logP would be a rate-limiting factor for the anti-Toxoplasma activity of this class of compounds.

  通过采用简单的合成方法，得到了一系列高效的卤代咪唑硫脲类化合物，对RH滴虫具有抗弓形虫效果，远优于磺胺二甲嘧啶（IC50为10.30-113.45 µg/mL，而磺胺二甲嘧啶为~2721.45 µg/mL）。其中最有效的化合物为12、13和15，其对弓形虫的体外增殖抑制作用甚至比替米考星（IC50为12.13 µg/mL）更为强烈。脂溶性研究的结果表明，对于这类化合物的抗弓形虫活性，logP可能是一个限制因素。
• 1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii
  作者：Lidia Węglińska、Adrian Bekier、Katarzyna Dzitko、Barbara Pacholczyk-Sienicka、Łukasz Albrecht、Tomasz Plech、Piotr Paneth、Agata Paneth

  DOI：10.3390/cells10051053

  日期：——

  Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b–12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC50) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b–12b, especially 12b with IC50 of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells.

  由食物和水源的寄生虫弓形虫（T. gondii）引起的先天性和获得性弓形虫病是全球最普遍的人兽共患病之一。T. gondii是一种有限的细胞内寄生虫，因此，成功、高效和强大的宿主细胞入侵过程对其生存、增殖和传播至关重要。在本研究中，我们筛选了一系列在C5位置带有咪唑环的新型1,3,4-噻二唑-2-卤代苯胺（1b-12b）对T. gondii宿主细胞入侵和增殖的影响。为了实现这一目标，这些化合物首先在体外进行细胞毒性试验，评估它们对人类成纤维细胞的细胞毒性，然后评估其抗寄生虫效力。结果显示，所有这些化合物在T. gondii生长抑制（IC50）和对寄生虫的选择性指数（SI）方面都比对照药物磺胺二甲嘧啶和替米考星表现更好。随后，具有间氟2b、间氯5b、间溴8b、间碘11b和对碘12b取代的最有效化合物进行了测试，以抑制滴虫的入侵和随后的增殖。所有化合物均通过对滴虫和寄生囊形成的直接作用显著抑制了寄生虫的入侵和细胞内增殖。其中最有效的是对碘衍生物12b，与未经处理的宿主细胞相比，它使感染宿主细胞的百分比减少了44％，每个囊泡中滴虫的数量减少了93％。总的来说，这些研究表明1,3,4-噻二唑1b-12b，特别是IC50为4.70 µg/mL，SI为20.89的12b，可以被认为是未来设计和合成有效且选择性地阻止T. gondii进入宿主细胞的抗弓形虫药物的早期药物。
• Synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities of thiosemicarbazides, 4-thiazolidinones and 1,3,4-thiadiazoles
  作者：André P. Liesen、Thiago M. de Aquino、Cristiane S. Carvalho、Vânia T. Lima、Janete M. de Araújo、José G. de Lima、Antônio R. de Faria、Edésio J.T. de Melo、Antonio J. Alves、Elias W. Alves、Anselmo Q. Alves、Alexandre J.S. Góes

  DOI：10.1016/j.ejmech.2010.05.017

  日期：2010.9

  In this work we reported the synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities in vitro of three new compound series obtained from ethyl(5-methyl-1-H-imidazole-4-carboxylate): acylthiosemicarbazide analogues 3a-d, 4-thiazolidinone analogues 4a-d and 1,3,4-thiadiazole analogues 5a-d. All synthesized compounds were characterized by IR, H-1, C-13 NMR and HRMS. The majority of the tested compounds show excellent anti-T gondii activity when compared to hydroxyurea and sulfadiazine. In addition it was also shown that most of the compounds in this study have a better performance against intracellular tachyzoites. The results for antimicrobial activity evaluation showed weak antibacterial and antifungal activities for all the tested molecules, when compared with the standard drugs (chloramphenicol and rifampicin for antibacterial activity; nistatin and ketoconazole for antifungal activity). (C) 2010 Elsevier Masson SAS. All rights reserved.
• Imidazole-Thiosemicarbazide Derivatives as Potent Anti-Mycobacterium tuberculosis Compounds with Antibiofilm Activity
  作者：Adrian Bekier、Malwina Kawka、Jakub Lach、Jarosław Dziadek、Agata Paneth、Justyna Gatkowska、Katarzyna Dzitko、Bożena Dziadek

  DOI：10.3390/cells10123476

  日期：——

  Mycobacterium tuberculosis (Mtb) is an intracellular pathogenic bacterium and the causative agent of tuberculosis. This disease is one of the most ancient and deadliest bacterial infections, as it poses major health, social and economic challenges at a global level, primarily in low- and middle-income countries. The lack of an effective vaccine, the long and expensive drug therapy, and the rapid spread of drug-resistant strains of Mtb have led to the re-emergence of tuberculosis as a global pandemic. Here, we assessed the in vitro activity of new imidazole-thiosemicarbazide derivatives (ITDs) against Mtb infection and their effects on mycobacterial biofilm formation. Cytotoxicity studies of the new compounds in cell lines and human monocyte-derived macrophages (MDMs) were performed. The anti-Mtb activity of ITDs was evaluated by determining minimal inhibitory concentrations of resazurin, time-kill curves, bacterial intracellular growth and the effect on biofilm formation. Mutation frequency and whole-genome sequencing of mutants that were resistant to ITDs were performed. The antimycobacterial potential of ITDs with the ability to penetrate Mtb-infected human macrophages and significantly inhibit the intracellular growth of tubercle bacilli and suppress Mtb biofilm formation was observed.

  结核分枝杆菌（Mtb）是一种细胞内病原菌，是结核病的病原体。这种疾病是最古老和最致命的细菌感染之一，因为它在全球范围内主要对低收入和中等收入国家构成了重大的健康、社会和经济挑战。缺乏有效的疫苗、长期昂贵的药物治疗和快速传播的耐药菌株导致结核病重新成为全球流行病。本研究评估了新的咪唑硫脲衍生物（ITDs）对Mtb感染的体外活性以及它们对分枝杆菌生物膜形成的影响。对新化合物在细胞系和人单核细胞源性巨噬细胞（MDMs）中的细胞毒性进行了研究。通过测定还原蓝的最小抑菌浓度、时间杀菌曲线、细菌细胞内生长和对生物膜形成的影响来评估ITDs的抗Mtb活性。进行了对ITDs耐药突变体的突变频率和全基因组测序。观察到具有穿透Mtb感染的人类巨噬细胞的能力、显著抑制结核杆菌细胞内生长和抑制Mtb生物膜形成的ITDs的抗分枝杆菌潜力。
• Inhibition of <i>Toxoplasma gondii</i> by 1,2,4-triazole-based compounds: marked improvement in selectivity relative to the standard therapy pyrimethamine and sulfadiazine
  作者：Lidia Węglińska、Adrian Bekier、Nazar Trotsko、Barbara Kaproń、Tomasz Plech、Katarzyna Dzitko、Agata Paneth

  DOI：10.1080/14756366.2022.2112576

  日期：2022.12.31