6-bromo-4-(2,6-difluorophenyl)-2-methoxyquinoline | 1227383-37-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-bromo-4-(2,6-difluorophenyl)-2-methoxyquinoline
• CAS: 1227383-37-0
• 化学式: C₁₆H₁₀BrF₂NO
• 分子量: 350.162
• InChiKey: RXKJKIVPUYQPHZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  22.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methanone 、 6-bromo-4-(2,6-difluorophenyl)-2-methoxyquinoline 在 正丁基锂 作用下， 以 四氢呋喃 为溶剂， 以49%的产率得到4-(2,6-difluorophenyl)-6-((4-chlorophenyl)(hydroxy)(1-methyl-1H-imidazol-5-yl)methyl)-2-methoxyquinoline
  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
• 作为产物：
  描述：

  6-bromo-4-(2,6-difluorophenyl)quinolin-2(1H)-one 、 trimethoxonium tetrafluoroborate 在 sodium hydroxide 作用下， 以 二氯甲烷 为溶剂， 反应 21.0h， 以50%的产率得到6-bromo-4-(2,6-difluorophenyl)-2-methoxyquinoline
  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

• 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.