2-amino-4-(4-chlorophenyl)thiazole-5-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-amino-4-(4-chlorophenyl)thiazole-5-carbonitrile
• 英文别名: 2-Amino-4-(4-chlorophenyl)-1,3-thiazole-5-carbonitrile；2-amino-4-(4-chlorophenyl)-1,3-thiazole-5-carbonitrile
• 化学式: C₁₀H₆ClN₃S
• 分子量: 235.697
• InChiKey: OHHIZLRCGPCZLS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  90.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-amino-4-(4-chlorophenyl)thiazole-5-carbonitrile 在 亚硝酸特丁酯 、 对甲苯磺酸 、 copper dichloride 作用下， 以 甲苯 、 乙腈 为溶剂， 反应 5.5h， 生成 (Z)-4-(4-chlorophenyl)-2-(2-(1-(1-ethyl-5-(4-((4-ethylpiperazin-1-yl)methyl)thiazol-2-yl)-1H-indol-3-yl)-2,2,2-trifluoroethylidene)hydrazinyl)thiazole-5-carbonitrile
  参考文献：
  名称：

  Structure guided design of potent indole-based ATX inhibitors bearing hydrazone moiety with tumor suppression effects

  摘要：

  ATX was capable of catalyzing the hydrolysis of LPC to the lipid mediator LPA which attracted considerable attention on the development of potent ATX inhibitors. Herein, driven by the HTS product indolebased lead 1, a hybridization strategy was utilized to construct the trifluoroacetyl hydrazone moiety through assembling the phenyl thiazole fragment to the indole skeleton of lead 1. After a systematic structure guided optimization, by cycling the phenyl thiazole to the compacted benzothiazole or decreasing the lipophilicity, two promising ATX inhibitors (9j and 25a) were identified with IC50 values of 2.1 nM and 19.0 nM, respectively. All compounds were tested a panel of cancer cell lines and a preliminary affinity on breast cancer cell lines (SI > 16.5) were observed which shed a light on their potential application of breast cancer relevant cases. Through a dedicated docking study, the intramolecular pseudo-ring within the trifluoroacetylhydrazone moiety played a significant role in constraining the binding poses of 9j and 25a. Finally, a binding free energy calculation was conducted to examine the contribution of different interactions in binding affinity. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112456
• 作为产物：
  描述：

  4-氯苯甲酸乙酯 在 碘 、 sodium hydride 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 4.0h， 生成 2-amino-4-(4-chlorophenyl)thiazole-5-carbonitrile
  参考文献：
  名称：

  Structure guided design of potent indole-based ATX inhibitors bearing hydrazone moiety with tumor suppression effects

  摘要：

  ATX was capable of catalyzing the hydrolysis of LPC to the lipid mediator LPA which attracted considerable attention on the development of potent ATX inhibitors. Herein, driven by the HTS product indolebased lead 1, a hybridization strategy was utilized to construct the trifluoroacetyl hydrazone moiety through assembling the phenyl thiazole fragment to the indole skeleton of lead 1. After a systematic structure guided optimization, by cycling the phenyl thiazole to the compacted benzothiazole or decreasing the lipophilicity, two promising ATX inhibitors (9j and 25a) were identified with IC50 values of 2.1 nM and 19.0 nM, respectively. All compounds were tested a panel of cancer cell lines and a preliminary affinity on breast cancer cell lines (SI > 16.5) were observed which shed a light on their potential application of breast cancer relevant cases. Through a dedicated docking study, the intramolecular pseudo-ring within the trifluoroacetylhydrazone moiety played a significant role in constraining the binding poses of 9j and 25a. Finally, a binding free energy calculation was conducted to examine the contribution of different interactions in binding affinity. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112456

文献信息

• TBHP/AIBN-Mediated Synthesis of 2-Amino-thioazoles from Active Methylene Ketones and Thiourea under Metal-free Conditions
  作者：Jiyun Sun、Huaibin Ge、Xiaohua Zhen、Xuechan An、Guangtao Zhang、Daisy Zhang-Negrerie、Yunfei Du、Kang Zhao

  DOI：10.1016/j.tet.2018.02.064

  日期：2018.4

  A new oxidative system of tert-butyl hydroperoxide (TBHP)/azodiisobutyronitrile (AIBN) has been used for the first time for a convenient, metal-free synthesis of substituted 2-aminothioazoles from active methylene ketone derivatives and thiourea. The reaction is postulated to proceed via an oxidative cyclization initiated by a radical process and followed by a condensation reaction.

  首次使用叔丁基过氧化氢（TBHP）/偶氮二异丁腈（AIBN）的新氧化系统，从活性亚甲基酮衍生物和硫脲方便，无金属地合成取代的2-氨基噻唑。假定该反应通过自由基过程引发的氧化环化进行，然后进行缩合反应。
• 一种合成2-氨基噻唑衍生物的方法
  申请人：天津大学

  公开号：CN107739350B

  公开（公告）日：2020-12-22

  本发明公开了一种合成2‑氨基噻唑衍生物的方法，步骤为：以α位带有吸电子取代基的酮类衍生物(I)与硫脲(II)为原料，以过氧叔丁醇为氧化剂，偶氮二异丁腈为自由基引发剂，在室温～回流的条件下，在溶剂甲醇中发生自由基偶联反应及脱水反应，生成2‑氨基噻唑衍生物(III)；反应式为：本发明利用非金属的偶氮二异丁腈和过氧叔丁醇的自由基氧化体系，避免了昂贵的过渡金属催化剂的使用，拓宽了底物的范围，使用羰基α位是吸电子取代基的底物即可，易离去基团不再是必须的。具有操作简单，反应原料以及反应试剂易得，收率较高等优点。
• 10.1021/acsmedchemlett.4c00220
  作者：Wang, Haiyang、Zhou, Yihui、Lu, Li、Cen, Jie、Wu, Zhenying、Yang, Bo、Zhu, Chengliang、Cao, Ji、Yu, Yongping、Chen, Wenteng

  DOI：10.1021/acsmedchemlett.4c00220

  日期：——

  anticancer target. Given the challenge of direct pharmacological inhibiting of MYC, impairing the interaction of MYC and its key cofactor WDR5 has been proposed as a promising strategy for MYC-driven cancer treatment. Herein, we report the discovery of 5-thiocyanatothiazol-2-amines that disrupt the WDR5-MYC interaction. Hit fragments were initially identified in a fluorescence polarization (FP)-based screening

  MYC扩增经常在大约 50% 的人类癌症中观察到，使其成为非常理想的抗癌靶点。鉴于直接药理抑制 MYC 的挑战，削弱 MYC 及其关键辅因子 WDR5 的相互作用已被提议作为 MYC 驱动的癌症治疗的一种有前景的策略。在此，我们报告了破坏 WDR5-MYC 相互作用的 5-硫氰酸噻唑-2-胺的发现。命中片段最初是在内部文库基于荧光偏振 (FP) 的筛选中鉴定出来的，结构-活性关系探索产生了对 WDR5-MYC 相互作用具有有效抑制活性的先导化合物4m和4o ( K i = 2.4 μM 为4m ； K i = 1.0 μM 为4o )。这些化合物通过差示扫描荧光法 (DSF) 和免疫共沉淀 (Co-IP) 得到进一步验证。此外， 4m和4o对多种MYC驱动的癌细胞系表现出良好的细胞活性，IC 50值在微摩尔水平（IC 50 = 0.71–7.40 μM）。我们的研究结果提供了一种潜在的阻断
• Structure guided design of potent indole-based ATX inhibitors bearing hydrazone moiety with tumor suppression effects
  作者：Hongrui Lei、Changtao Li、Yu Yang、Fang Jia、Ming Guo、Minglin Zhu、Nan Jiang、Xin Zhai

  DOI：10.1016/j.ejmech.2020.112456

  日期：2020.9

  ATX was capable of catalyzing the hydrolysis of LPC to the lipid mediator LPA which attracted considerable attention on the development of potent ATX inhibitors. Herein, driven by the HTS product indolebased lead 1, a hybridization strategy was utilized to construct the trifluoroacetyl hydrazone moiety through assembling the phenyl thiazole fragment to the indole skeleton of lead 1. After a systematic structure guided optimization, by cycling the phenyl thiazole to the compacted benzothiazole or decreasing the lipophilicity, two promising ATX inhibitors (9j and 25a) were identified with IC50 values of 2.1 nM and 19.0 nM, respectively. All compounds were tested a panel of cancer cell lines and a preliminary affinity on breast cancer cell lines (SI > 16.5) were observed which shed a light on their potential application of breast cancer relevant cases. Through a dedicated docking study, the intramolecular pseudo-ring within the trifluoroacetylhydrazone moiety played a significant role in constraining the binding poses of 9j and 25a. Finally, a binding free energy calculation was conducted to examine the contribution of different interactions in binding affinity. (C) 2020 Elsevier Masson SAS. All rights reserved.