2-chloro-N-(3-bromopropionyl)amidophenothiazine | 3534-16-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 2-chloro-N-(3-bromopropionyl)amidophenothiazine
• 英文别名: 10-(3-bromo-propionyl)-2-chloro-10H-phenothiazine；3-Chlor-10-<3-brom-propionyl>-phenthiazin；2-Chlor-10-(3-brom-propionyl)-phenothiazin；3-Bromo-1-(2-chloro-10H-phenothiazin-10-yl)-1-propanone；3-bromo-1-(2-chlorophenothiazin-10-yl)propan-1-one
• CAS: 3534-16-5
• 化学式: C₁₅H₁₁BrClNOS
• 分子量: 368.681
• InChiKey: JBIHGHDQILYKJR-UHFFFAOYSA-N

物化性质

• 熔点：
  112 °C(Solv: cyclohexane (110-82-7))
• 沸点：
  564.7±50.0 °C(Predicted)
• 密度：
  1.606±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  45.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-chloro-N-(3-bromopropionyl)amidophenothiazine 在 硼烷 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以99%的产率得到2-chloro-N-(3-bromopropyl)aminophenothiazine
  参考文献：
  名称：

  Use of an Additional Hydrophobic Binding Site, the Z Site, in the Rational Drug Design of a New Class of Stronger Trypanothione Reductase Inhibitor, Quaternary Alkylammonium Phenothiazines

  摘要：

  Improved rationally designed lead drug structures against African trypanosomiasis, Chagas disease, and leishmaniasis were obtained against trypanothione reductase from Trypanosoma cruzi. Substituted-benzyl [3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl] dimethyl ammonium salts, synthesized by Menschutkin quaternization of the tertiary alkylamine omega-nitrogen atom of chlorpromazine, were linear, competitive inhibitors of recombinant trypanothione reductase from T. cruzi, with either trypanothione disulfide or N-benzyloxycarbonyl-L-cysteinylglycyl 3-dimethylaminopropylamide disulfide as substrate. The permanent positive charge on the distal nitrogen atom of the tricyclic side chain contribution to binding was estimated as greater than or equal to 5.6 kcal.mol(-1) by comparison with the analogue with the cationic nitrogen atom of the quaternary replaced by an ether oxygen atom. A further major contribution to improving K-i values and inhibition strength was the hydrophobic natures and structures of the N-benzyl substituents. The strongest inhibitor, the (3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl]-(3,4-dichlorobenzyl)dimethylammonium derivative (K-i 0.12 mu M), was similar to 2 orders of magnitude more inhibitory than the parent chlorpromazine. Several of these quaternary phenothiazines completely inhibited T. brucei parasite growth in vitro at < 1 mu M Antiparasite activity was not solely determined by inhibition strength against trypanothione reductase, there being a strong contribution from hydrophobicity (for example, benzhydryl-quaternized chlorpromazime had ED50 < 1 mu M). Although active against Leishmania donovani, none of the analogues showed major improvement in this activity relative to chlorpromazine or other nonquaternized phenothiazines. The p-tert-butylbenzyl-quaternized analogue very strongly inhibited (ED50 < 1 mu M) growth of the amastigote stage of T. cruzi.

  DOI：

  10.1021/jm000156+
• 作为产物：
  描述：

  2-氯吩噻嗪 、 3-溴丙酰氯 以 氯仿 为溶剂， 反应 0.67h， 以90%的产率得到2-chloro-N-(3-bromopropionyl)amidophenothiazine
  参考文献：
  名称：

  Use of an Additional Hydrophobic Binding Site, the Z Site, in the Rational Drug Design of a New Class of Stronger Trypanothione Reductase Inhibitor, Quaternary Alkylammonium Phenothiazines

  摘要：

  Improved rationally designed lead drug structures against African trypanosomiasis, Chagas disease, and leishmaniasis were obtained against trypanothione reductase from Trypanosoma cruzi. Substituted-benzyl [3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl] dimethyl ammonium salts, synthesized by Menschutkin quaternization of the tertiary alkylamine omega-nitrogen atom of chlorpromazine, were linear, competitive inhibitors of recombinant trypanothione reductase from T. cruzi, with either trypanothione disulfide or N-benzyloxycarbonyl-L-cysteinylglycyl 3-dimethylaminopropylamide disulfide as substrate. The permanent positive charge on the distal nitrogen atom of the tricyclic side chain contribution to binding was estimated as greater than or equal to 5.6 kcal.mol(-1) by comparison with the analogue with the cationic nitrogen atom of the quaternary replaced by an ether oxygen atom. A further major contribution to improving K-i values and inhibition strength was the hydrophobic natures and structures of the N-benzyl substituents. The strongest inhibitor, the (3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl]-(3,4-dichlorobenzyl)dimethylammonium derivative (K-i 0.12 mu M), was similar to 2 orders of magnitude more inhibitory than the parent chlorpromazine. Several of these quaternary phenothiazines completely inhibited T. brucei parasite growth in vitro at < 1 mu M Antiparasite activity was not solely determined by inhibition strength against trypanothione reductase, there being a strong contribution from hydrophobicity (for example, benzhydryl-quaternized chlorpromazime had ED50 < 1 mu M). Although active against Leishmania donovani, none of the analogues showed major improvement in this activity relative to chlorpromazine or other nonquaternized phenothiazines. The p-tert-butylbenzyl-quaternized analogue very strongly inhibited (ED50 < 1 mu M) growth of the amastigote stage of T. cruzi.

  DOI：

  10.1021/jm000156+

文献信息

• Use of an Additional Hydrophobic Binding Site, the Z Site, in the Rational Drug Design of a New Class of Stronger Trypanothione Reductase Inhibitor, Quaternary Alkylammonium Phenothiazines
  作者：M. Omar F. Khan、Susan E. Austin、Cecil Chan、Hong Yin、Debora Marks、Sheetal N. Vaghjiani、Howard Kendrick、Vanessa Yardley、Simon L. Croft、Kenneth T. Douglas

  DOI：10.1021/jm000156+

  日期：2000.8.1

  Improved rationally designed lead drug structures against African trypanosomiasis, Chagas disease, and leishmaniasis were obtained against trypanothione reductase from Trypanosoma cruzi. Substituted-benzyl [3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl] dimethyl ammonium salts, synthesized by Menschutkin quaternization of the tertiary alkylamine omega-nitrogen atom of chlorpromazine, were linear, competitive inhibitors of recombinant trypanothione reductase from T. cruzi, with either trypanothione disulfide or N-benzyloxycarbonyl-L-cysteinylglycyl 3-dimethylaminopropylamide disulfide as substrate. The permanent positive charge on the distal nitrogen atom of the tricyclic side chain contribution to binding was estimated as greater than or equal to 5.6 kcal.mol(-1) by comparison with the analogue with the cationic nitrogen atom of the quaternary replaced by an ether oxygen atom. A further major contribution to improving K-i values and inhibition strength was the hydrophobic natures and structures of the N-benzyl substituents. The strongest inhibitor, the (3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl]-(3,4-dichlorobenzyl)dimethylammonium derivative (K-i 0.12 mu M), was similar to 2 orders of magnitude more inhibitory than the parent chlorpromazine. Several of these quaternary phenothiazines completely inhibited T. brucei parasite growth in vitro at < 1 mu M Antiparasite activity was not solely determined by inhibition strength against trypanothione reductase, there being a strong contribution from hydrophobicity (for example, benzhydryl-quaternized chlorpromazime had ED50 < 1 mu M). Although active against Leishmania donovani, none of the analogues showed major improvement in this activity relative to chlorpromazine or other nonquaternized phenothiazines. The p-tert-butylbenzyl-quaternized analogue very strongly inhibited (ED50 < 1 mu M) growth of the amastigote stage of T. cruzi.