N1-(4'-cyanophenyl)-5-(4''-(2-cyanovinyl)-2'',6''-dimethylphenoxy)-4-methoxycarbonyl-2-nitroaniline | 1372406-97-7

• 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: N1-(4'-cyanophenyl)-5-(4''-(2-cyanovinyl)-2'',6''-dimethylphenoxy)-4-methoxycarbonyl-2-nitroaniline
• 英文别名: methyl 4-(4-cyanoanilino)-2-[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenoxy]-5-nitrobenzoate
• CAS: 1372406-97-7
• 化学式: C₂₆H₂₀N₄O₅
• 分子量: 468.469
• InChiKey: XLFRVMMDGAUHNU-SNAWJCMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  141
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N1-(4'-cyanophenyl)-5-(4''-(2-cyanovinyl)-2'',6''-dimethylphenoxy)-4-methoxycarbonyl-2-nitroaniline 在 氯化亚砜 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 7.5h， 生成 N1-(4'-cyanophenyl)-5-(4''-(2-cyanovinyl)-2'',6''-dimethylphenoxy)-4-methylcarbamoyl-2-nitroaniline
  参考文献：
  名称：

  Design, Synthesis, and Preclinical Evaluations of Novel 4-Substituted 1,5-Diarylanilines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates

  摘要：

  Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wildtype and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Drug like physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1-90 mu g/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 A(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.

  DOI：

  10.1021/jm3007678
• 作为产物：
  描述：

  2,4-二氯-5-硝基苯甲酸 在 硫酸 、 potassium tert-butylate 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.75h， 生成 N1-(4'-cyanophenyl)-5-(4''-(2-cyanovinyl)-2'',6''-dimethylphenoxy)-4-methoxycarbonyl-2-nitroaniline
  参考文献：
  名称：

  Design, Synthesis, and Preclinical Evaluations of Novel 4-Substituted 1,5-Diarylanilines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates

  摘要：

  Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wildtype and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Drug like physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1-90 mu g/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 A(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.

  DOI：

  10.1021/jm3007678

文献信息

• Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus
  作者：Lei Wei、Hui-Ling Wang、Li Huang、Chin-Ho Chen、Susan L. Morris-Natschke、Kuo-Hsiung Lee、Lan Xie

  DOI：10.1016/j.bmcl.2017.04.068

  日期：2017.6

  On the basis of our prior structure-activity relationship (SAR) results, our current lead optimization of 1,5-diarylanilines (DAANs) focused on the 4-substituent (R-1) on the central phenyl ring as a modifiable position related simultaneously to improved drug resistance profiles and drug-like properties. Newly synthesized p-cyanovinyl-DAANs (8a-8g) with different R-1 side chains plus prior active p-cyanoethyl-DAANs (4a-4c) were evaluated not only for anti-HIV potency against both wild-type HIV virus and rilpivirine-resistant (E138K, E138K+M184I) viral replication, but also for multiple drug-like properties, including aqueous solubility, lipophilicity, and metabolic stability in human liver microsomes and human plasma. This study revealed that both ester and amide R-1 substituents led to low nanomolar anti-HIV potency against wild-type and rilpivirine-resistant viral strains (E138K-resistance fold changes < 3). The N-substituted amide-R-1 side chains were superior to ester-R-1 likely due to improved aqueous solubility, lipophilicity, and higher metabolic stability in vitro. Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties. (C) 2017 Elsevier Ltd. All rights reserved.
• Design, Synthesis, and Preclinical Evaluations of Novel 4-Substituted 1,5-Diarylanilines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) Drug Candidates
  作者：Lian-Qi Sun、Lei Zhu、Keduo Qian、Bingjie Qin、Li Huang、Chin Ho Chen、Kuo-Hsiung Lee、Lan Xie

  DOI：10.1021/jm3007678

  日期：2012.8.23

  Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wildtype and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC50 values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC50 values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Drug like physicochemical property assessments revealed that the most active DAANs (EC50 < 10 nM) have better aqueous solubility (>1-90 mu g/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 A(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.