4-(3-chloro-2-methylphenyl)-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-1-methylquinolin-2(1H)-one | 1118761-93-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二芳基庚烷
• 英文名称: 4-(3-chloro-2-methylphenyl)-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-1-methylquinolin-2(1H)-one
• 英文别名: 4-(3-Chloro-2-methylphenyl)-6-[(4-chlorophenyl)-hydroxy-(3-methylimidazol-4-yl)methyl]-1-methylquinolin-2-one
• CAS: 1118761-93-5
• 化学式: C₂₈H₂₃Cl₂N₃O₂
• 分子量: 504.416
• InChiKey: WXGAEOKBYIMZFF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  58.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(3-chloro-2-methylphenyl)-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-1-methylquinolin-2(1H)-one 在 氯化亚砜 作用下， 反应 12.0h， 生成
  参考文献：
  名称：

  Rational Modification of a Candidate Cancer Drug for Use Against Chagas Disease

  摘要：

  Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14 alpha-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.

  DOI：

  10.1021/jm801313t
• 作为产物：
  描述：

  4-(3-chloro-2-methylphenyl)-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)quinolin-2(1H)-one 、 碘甲烷 在 苄基三乙基氯化铵 、 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 0.17h， 以59%的产率得到4-(3-chloro-2-methylphenyl)-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-1-methylquinolin-2(1H)-one
  参考文献：
  名称：

  Second Generation Analogues of the Cancer Drug Clinical Candidate Tipifarnib for Anti-Chagas Disease Drug Discovery

  摘要：

  We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14 alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14 alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.

  DOI：

  10.1021/jm9013136

文献信息

• Rational Modification of a Candidate Cancer Drug for Use Against Chagas Disease
  作者：James M. Kraus、Christophe L. M. J. Verlinde、Mandana Karimi、Galina I. Lepesheva、Michael H. Gelb、Frederick S. Buckner

  DOI：10.1021/jm801313t

  日期：2009.3.26

  Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14 alpha-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
• Second Generation Analogues of the Cancer Drug Clinical Candidate Tipifarnib for Anti-Chagas Disease Drug Discovery
  作者：James M. Kraus、Hari Babu Tatipaka、Sarah A. McGuffin、Naveen Kumar Chennamaneni、Mandana Karimi、Jenifer Arif、Christophe L. M. J. Verlinde、Frederick S. Buckner、Michael H. Gelb

  DOI：10.1021/jm9013136

  日期：2010.5.27

  We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14 alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14 alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.