4-((2-chloroquinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile | 1239860-98-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-((2-chloroquinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile
• 英文别名: 4-(2-Chloroquinazolin-4-yl)oxy-3,5-dimethylbenzonitrile
• CAS: 1239860-98-0
• 化学式: C₁₇H₁₂ClN₃O
• 分子量: 309.755
• InChiKey: QGHIJDYCVKHSGS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  58.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-((2-chloroquinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile 在 potassium carbonate 、 caesium carbonate 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3,5-dimethyl-4-((2-((1-(2-morpholino-2-oxoethyl)piperidin-4-yl)amino)quinazolin-4-yl)oxy)benzonitrile
  参考文献：
  名称：

  Targeting dual tolerant regions of binding pocket: Discovery of novel morpholine-substituted diarylpyrimidines as potent HIV-1 NNRTIs with significantly improved water solubility

  摘要：

  To address the intractable issues of drug resistance and poor solubility, a novel series of morpholine-substituted diarylpyrimidines targeting the tolerant region I and tolerant region II of NNIBP were rationally designed by utilizing the available crystallography studies. The biological evaluation results showed that four most promising compounds (14e1, 14g1, 14g2 and 14j2) displayed excellent potency against WT HIV-1 strain with EC(50 )values ranging from 58 to 87 nM, being far more potent than NVP and comparable to ETV. Besides, some derivatives exhibited moderate activity in inhibiting the mutant HIV-1 strains. More encouragingly, 14d2 (RF = 0.4) possessed higher antiresistance profile than ETV (RF = 6.3) and K-5a2 (RF = 3.0) toward the double mutant strain F227L + V106A. The HIV-1 RT inhibition assay confirmed their binding target. The molecular docking studies were conducted and discussed in detail to rationalize the preliminary SARs. Further test indicated that morpholine could indeed promote the improvement of water solubility. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features. (C) 2020 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2020.112811
• 作为产物：
  描述：

  2,4-二氯喹唑啉 、 3,5-二甲基-4-羟基苯甲腈 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以90 %的产率得到4-((2-chloroquinazolin-4-yl)oxy)-3,5-dimethylbenzonitrile
  参考文献：
  名称：

  含硼酸二芳基嘧啶衍生物作为新型 HIV-1 非核苷逆转录酶抑制剂的鉴定

  摘要：

  本研究将特权硼酸酯引入依曲韦林 (ETR) 的右翼，得到一系列新型含硼酸酯衍生物。使用 MTT 方法评估了这些新合成的衍生物在 MT-4 细胞中的抗 HIV 效力，并通过 ELISA 方法测定了它们对 HIV-1 逆转录酶 (RT) 的抑制活性。大多数合成化合物对野生型和广泛的 HIV-1 突变株显示出有前途的抗病毒活性。特别是，4a对野生型和一组单突变（L100I、K103N、Y181C 和 E138K）表现出最强的活性，EC 50值范围为 0.005 至 0.648 μM，远优于奈韦拉平（ EC 50= 0.151 微米）。此外，事实证明4b是针对双突变菌株 F227L + V106A 和 RES056 的有效抑制剂，EC 50值分别为 3.21 和 2.30 μM。还研究了 RT 抑制活性和分子对接。

  DOI：

  10.3390/molecules27217538

文献信息

• Discovery and Characterization of Fluorine-Substituted Diarylpyrimidine Derivatives as Novel HIV-1 NNRTIs with Highly Improved Resistance Profiles and Low Activity for the hERG Ion Channel
  作者：Dongwei Kang、F. Xavier Ruiz、Da Feng、Alyssa Pilch、Tong Zhao、Fenju Wei、Zhao Wang、Yanying Sun、Zengjun Fang、Erik De Clercq、Christophe Pannecouque、Eddy Arnold、Xinyong Liu、Peng Zhan

  DOI：10.1021/acs.jmedchem.9b01769

  日期：2020.2.13

  development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies

  我们之前的努力导致了两种有效的 NNRTI 的开发，即 K-5a2 和 25a，与依曲韦林相比，它们表现出有效的抗 HIV-1 效力和耐药性。然而，这两种抑制剂均存在强效 hERG 抑制作用且半衰期短。本文以K-5a2和依曲韦林为先导，通过分子杂交和生物电子等排策略设计了一系列新型氟取代二芳基嘧啶衍生物。结果表明24b是最活跃的抑制剂，对耐药菌株表现出广谱活性（EC50 = 3.60-21.5 nM），显着降低细胞毒性（CC50 = 155 μM），并降低hERG抑制（IC50 > 30 μM）。晶体学研究证实了 24b 的结合和氟原子的作用，以及腈基与 H235 主链羰基的最佳接触。此外，24b 显示出更长的半衰期和良好的安全特性。所有结果都表明，24b 作为抗 HIV-1 候选药物在规避耐药性方面具有重大前景。
• 一种喹唑啉类HIV-1抑制剂及其制备方法和 应用
  申请人：山东大学

  公开号：CN108440500B

  公开（公告）日：2021-03-16

  本发明涉及一种喹唑啉类HIV‑1抑制剂及其制备方法和应用。所述化合物具有式I所示的结构。本发明还涉及含有式I结构化合物的药物组合物。本发明还提供上述化合物以及含有一个或多个此类化合物的组合物在制备治疗和预防人免疫缺陷病毒(HIV)药物中的应用。
• Boronic acid-containing diarylpyrimidine derivatives as novel HIV-1 NNRTIs: Design, synthesis and biological evaluation
  作者：Da Feng、Fenju Wei、Yanying Sun、Prem Prakash Sharma、Tao Zhang、Hao Lin、Brijesh Rathi、Erik De Clercq、Christophe Pannecouque、Dongwei Kang、Peng Zhan、Xinyong Liu

  DOI：10.1016/j.cclet.2021.02.033

  日期：2021.12
• Hybrid diarylbenzopyrimidine non-nucleoside reverse transcriptase inhibitors as promising new leads for improved anti-HIV-1 chemotherapy
  作者：Zhao-Sen Zeng、Qiu-Qin He、Yong-Hong Liang、Xiao-Qing Feng、Fen-Er Chen、Erik De Clercq、Jan Balzarini、Christophe Pannecouque

  DOI：10.1016/j.bmc.2010.05.081

  日期：2010.7

  Molecular hybridization of the known anti-HIV-1 template DPC083 and etravirine based on docking model overlay has been generated a novel series of diarylbenzopyrimidine analogues (DABPs) (5a-z). These new hybrids were assessed for their activity against HIV in MT-4 cell cultures. Most of these compounds showed good activity against wild-type HIV-1 and mutant viruses. In particular, compound 5r showed the most potent activity against wild-type HIV-1 with an EC50 value of 1.8 nM, and with a selectivity index up to 111,954. It also proved more active against mutant L100I, K103N, Y188L, and K103N + Y181C RT HIV-1 strains than efavirenz. (C) 2010 Elsevier Ltd. All rights reserved.