isopropyl 2-chloro-4-methyl-6-(3-nitrophenyl)pyrimidine-5-carboxylate | 1376766-58-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: isopropyl 2-chloro-4-methyl-6-(3-nitrophenyl)pyrimidine-5-carboxylate
• CAS: 1376766-58-3
• 化学式: C₁₅H₁₄ClN₃O₄
• 分子量: 335.747
• InChiKey: GTASZULDXOHQAH-UHFFFAOYSA-N

物化性质

• 沸点：
  500.0±50.0 °C(Predicted)
• 密度：
  1.329±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.58
• 重原子数：
  23.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  95.22
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  isopropyl 2-chloro-4-methyl-6-(3-nitrophenyl)pyrimidine-5-carboxylate 、 4-(4-氨基丁基)氨基-7-氯喹啉 在 potassium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 以78%的产率得到5-isopropyloxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-[4-(7-chloroquinolin-4-ylamino)butylamino]pyrimidine
  参考文献：
  名称：

  2-Aminopyrimidine based 4-aminoquinoline anti-plasmodial agents. Synthesis, biological activity, structure–activity relationship and mode of action studies

  摘要：

  2-Aminopyrimidine based 4-aminoquinolines were synthesized using an efficacious protocol. Some of the compounds showed in vitro anti-plasmodial activity against drug-sensitive CQ(S) (3D7) and drug-resistant CQ(R) (K1) strains of Plasmodium falciparum in the nM range. In particular, 5-isopropyloxycarbonyl-6-methyl-4-(2-nitrophenyl)-2-[(7-chloroquinolin-4-ylamino)butylamino] pyrimidine depicted the lowest IC50 (3.6 nM) value (56-fold less than CQ) against CQ(R) strain. Structure activity profile and binding with heme, mu-oxo-heme have been studied. Binding assays with DNA revealed better binding with target parasite type AT rich pUC18 DNA. Most compounds were somewhat cytotoxic, but especially cytostatic. Molecular docking analysis with Pf DHFR allowed identification of stabilizing interactions. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.03.007
• 作为产物：
  描述：

  6-methyl-4-(3-nitrophenyl)-2-oxo-1,2-dihydropyrimidine-5-carboxylic acid isopropyl ester 在 三氯氧磷 作用下， 生成 isopropyl 2-chloro-4-methyl-6-(3-nitrophenyl)pyrimidine-5-carboxylate
  参考文献：
  名称：

  异烟肼的结构阐述：异烟肼-嘧啶偶联物的合成、计算机分子对接和抗分枝杆菌活性。

  摘要：

  鉴于不可避免的耐药性出现，通过对现有药物进行结构调节来设计基于小分子的新候选药物已经引起了相当大的关注。一系列新的异烟肼-嘧啶缀合物以良好的产率合成，并使用微孔板 Alamar Blue 测定评估了抗结核分枝杆菌 H37Rv 菌株的抗结核活性。结构-抗 TB 关系曲线显示，在嘧啶支架的 C-6 处带有苯基的偶联物 8a 和 8c 是最活跃的 (MIC99 10 µM)，并且是该系列中细胞毒性最低的成员。在牛乳过氧化物酶的活性位点中 8a 以及细胞色素 C 过氧化物酶突变体 N184R Y36A 的计算机对接揭示了类似于激活异烟肼的血红素酶过氧化氢酶过氧化物酶 (KatG) 的有利相互作用。

  DOI：

  10.1007/s11030-019-10004-1

文献信息

• Primaquine–pyrimidine hybrids: Synthesis and dual-stage antiplasmodial activity
  作者：Hardeep Kaur、Marta Machado、Carmen de Kock、Peter Smith、Kelly Chibale、Miguel Prudêncio、Kamaljit Singh

  DOI：10.1016/j.ejmech.2015.06.045

  日期：2015.8

  A series of novel pyrimidine primaquine hybrids were synthesized and their effectiveness against the blood and liver stages of malaria parasites was evaluated. The hybrids displayed enhanced liver stage in vitro activity against P. berghei liver stage infection. (C) 2015 Elsevier Masson SAS. All rights reserved.
• Molecular Design and Synthesis of Ivermectin Hybrids Targeting Hepatic and Erythrocytic Stages of <i>Plasmodium</i> Parasites
  作者：Lovepreet Singh、Diana Fontinha、Denise Francisco、Antonio M. Mendes、Miguel Prudêncio、Kamaljit Singh

  DOI：10.1021/acs.jmedchem.0c00033

  日期：2020.2.27

  Ivermectin is a powerful endectocide, which reduces the incidence of vector-borne diseases. Besides its strong insecticidal effect on mosquito vectors of the disease, ivermectin inhibits Plasmodium falciparum sporogonic and blood stage development and impairs Plasmodium berghei development inside hepatocytes, both in vitro and in vivo. Herein, we present the first report on structural modification of ivermectin to produce dual action molecular hybrids with good structure-dependent in vitro activity against both the hepatic and erythrocytic stages of P. berghei and P. falciparum infection, suggesting inclusion of ivermectin antimalarial hybrids in malaria control strategies. The most active hybrid displayed over threefold and 10-fold higher in vitro activity than ivermectin against hepatic and blood stage infections, respectively. Although an overwhelming insecticidal effect against Anopheles stephensi mosquitoes in laboratory conditions was not noticed, in silico docking analysis supports allosteric binding to glutamate-gated chloride channels similar to ivermectin.