3-(4-amino-3-chloro-5-methylphenyl)acrylonitrile | 1609687-15-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(4-amino-3-chloro-5-methylphenyl)acrylonitrile
• 英文别名: 3-(4-amino-3-fluoro-5-methylphenyl)acrylonitrile；(E)-3-(4-amino-3-fluoro-5-methylphenyl)acrylonitrile；(E)-3-(4-amino-3-fluoro-5-methylphenyl)prop-2-enenitrile
• CAS: 1609687-15-1
• 化学式: C₁₀H₉FN₂
• 分子量: 176.193
• InChiKey: IZZVCQAWXIHSOO-NSCUHMNNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,4-二氯-6-氟喹唑啉 、 3-(4-amino-3-chloro-5-methylphenyl)acrylonitrile 在 potassium phosphate 、 palladium diacetate 、 2-二环己膦基-2'-(N,N-二甲胺)-联苯 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 12.0h， 生成
  参考文献：
  名称：

  Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles

  摘要：

  Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnudeoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound lid, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 mu L/min/mg (human) and 33.2 mu L/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 mu L/min/mg; rat, 33.2 mu L/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.

  DOI：

  10.1021/acsinfecdis.9b00229
• 作为产物：
  描述：

  2-氟-6-甲基苯胺 在 palladium 10% on activated carbon 、 四丁基溴化铵 、 sodium acetate 、 一氯化碘 、 碳酸氢钠 、 三(邻甲基苯基)磷 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 为溶剂， 反应 18.0h， 生成 3-(4-amino-3-chloro-5-methylphenyl)acrylonitrile
  参考文献：
  名称：

  Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles

  摘要：

  Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnudeoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound lid, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 mu L/min/mg (human) and 33.2 mu L/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 mu L/min/mg; rat, 33.2 mu L/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.

  DOI：

  10.1021/acsinfecdis.9b00229

文献信息

• [EN] NOVEL ANTI-HIV COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS ANTI-VIH
  申请人：UNIV ANTWERPEN

  公开号：WO2014072419A1

  公开（公告）日：2014-05-15

  The present invention relates to the field of HIV-1 infections, and in particular provides novel compounds containing fluorine on the Central ring. The compounds according to this invention are very suitable for the prevention and/or treatment of HIV-1 infection and in particular show higher activity against NNRTI-resistant strains of HIV-1.

  本发明涉及HIV-1感染领域，特别提供了在中心环上含氟的新化合物。根据本发明的化合物非常适用于预防和/或治疗HIV-1感染，特别对抗NNRTI耐药株的活性更高。
• 2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors
  作者：Sergey Sergeyev、Ashok Kumar Yadav、Philippe Franck、Johan Michiels、Paul Lewi、Jan Heeres、Guido Vanham、Kevin K. Ariën、Christophe M. L. Vande Velde、Hans De Winter、Bert U. W. Maes

  DOI：10.1021/acs.jmedchem.5b01336

  日期：2016.3.10

  New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential

  新的非核苷逆转录酶抑制剂（NNRTI），其结构与先前描述的二（芳基氨基）嘧啶相似，但具有2,6-二（芳基氨基）-3-氟吡啶，2,4-二（芳基氨基）-5报道了用2-氟嘧啶或1，3-二（芳基氨基）-4-氟苯部分代替2，4-二取代的嘧啶部分。新型NNRTI的简短实用合成依赖于两个连续的Pd催化胺化作为关键步骤。通过与参考化合物直接比较证明，氟原子的存在增加了针对野生型病毒和耐药突变株的体外抗HIV活性。
• Fragment hopping-based discovery of novel sulfinylacetamide-diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors
  作者：Sheng Han、Yali Sang、Yan Wu、Yuan Tao、Christophe Pannecouque、Erik De Clercq、Chunlin Zhuang、Fen-Er Chen

  DOI：10.1016/j.ejmech.2019.111874

  日期：2020.1

  fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less

  片段跳跃法被广泛应用于药物开发中。通过将硫代乙酰胺支架跳至新型人类免疫缺陷病毒1型（HIV-1）非核苷逆转录酶抑制剂（NNRTIs），可以解决一系列的二芳基嘧啶（DAPYs），从而解决了依特韦林和利吡韦林的细胞毒性问题。尽管在第一轮优化中的新化合物（11a-1）具有较弱的抗病毒活性，但它们显示出低得多的细胞毒性。对硫的进一步优化导致亚磺酰基乙酰胺-DAPYs表现出改善的抗病毒活性和更高的选择性指数，尤其是对K103N突变株。最有效的化合物12a对WT的EC50值为0.0249μM，对K103N突变株的EC50值为0.0104μM，细胞毒性低（CC50> 221μM）和高选择性指数（SI WT> 8873，SI K103N> 21186）。此外，该化合物在物种间显示出良好的体外微粒体稳定性。计算研究预测了这些有效化合物与HIV-1逆转录酶的结合模型，从而为新进展提供了进一步的见识。