1-(3,4-dichloro-phenyl)-6,6-dimethyl-1,6-dihydro-[1,3,5]triazine-2,4-diyldiamine; hydrochloride | 17711-81-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-(3,4-dichloro-phenyl)-6,6-dimethyl-1,6-dihydro-[1,3,5]triazine-2,4-diyldiamine; hydrochloride
• 英文别名: 1-(3,4-Dichlor-phenyl)-6,6-dimethyl-1,6-dihydro-[1,3,5]triazin-2,4-diyldiamin; Hydrochlorid；1-(3,4-Dichlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine;hydrochloride
• CAS: 17711-81-8
• 化学式: C₁₁H₁₃Cl₂N₅*ClH
• 分子量: 322.625
• InChiKey: QNPHBRAPEGFQDV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.39
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  79.4
• 氢给体数：
  3
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  二聚氰胺 、 丙酮 、 3,4-二氯苯胺 在 盐酸 作用下， 以71%的产率得到1-(3,4-dichloro-phenyl)-6,6-dimethyl-1,6-dihydro-[1,3,5]triazine-2,4-diyldiamine; hydrochloride
  参考文献：
  名称：

  Development of a Lead Inhibitor for the A16V+S108T Mutant of Dihydrofolate Reductase from the Cycloguanil-Resistant Strain (T9/94) of Plasmodium falciparum^†

  摘要：

  The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dihydrofolate reductase (DHFR) is a key mutant responsible for cycloguanil-resistant malaria due to steric interaction between Val-16 and one of the C-2 methyl groups of cycloguanil. 4,6-Diamino-1,2-dihydrotriazines have been prepared, in which both methyl groups of cycloguanil are replaced by H or by H and an alkyl or phenyl group, and their inhibition constants against wild-type and mutant DHFR determined. The S108T mutation is considered to decrease cycloguanil binding further through the effect on the orientation of the p-chlorophenyl group. By moving the p-chloro-substituent to the m-position in the chlorophenyl group, the activity against the A16V+S108T mutant enzyme is improved, and this effect is reinforced by the p-chloro substituent in the 3,4-dichlorophenyl group. A lead compound has been found with inhibitory activity similar to that of cycloguanil against the wild-type DHFR and about 120-fold more effective than cycloguanil against the A16V+S108T mutant enzyme. The activity of this compound against P. falciparum clone (T9/94 RC17) which harbors the A16V+S108T DHFR is about 85-fold greater than cycloguanil.

  DOI：

  10.1021/jm0009181

文献信息

• Structural Insights into the Development of Cycloguanil Derivatives as<i>Trypanosoma brucei</i>Pteridine-Reductase-1 Inhibitors
  作者：Giacomo Landi、Pasquale Linciano、Chiara Borsari、Claudia P. Bertolacini、Carolina B. Moraes、Anabela Cordeiro-da-Silva、Sheraz Gul、Gesa Witt、Maria Kuzikov、Maria Paola Costi、Cecilia Pozzi、Stefano Mangani

  DOI：10.1021/acsinfecdis.8b00358

  日期：2019.7.12

  Cycloguanil is a known dihydrofolate-reductase (DHFR) inhibitor, but there is no evidence of its activity on pteridine reductase (PTR), the main metabolic bypass to DHFR inhibition in trypanosomatid parasites. Here, we provide experimental evidence of cycloguanil as an inhibitor of Trypanosoma brucei PTR1 (TbPTR1). A small library of cycloguanil derivatives was developed, resulting in 1 and 2a having IC50 values of 692 and 186 nM, respectively, toward TbPTR1. Structural analysis revealed that the increased potency of 1 and 2a is due to the combined contributions of hydrophobic interactions, H-bonds, and halogen bonds. Moreover, in vitro cell-growth-inhibition tests indicated that 2a is also effective on T. brucei. The simultaneous inhibition of DHFR and PTR1 activity in T. brucei is a promising new strategy for the treatment of human African trypanosomiasis. For this purpose, 1,6-dihydrotriazines represent new molecular tools to develop potent dual PTR and DHFR inhibitors.
• Development of a Lead Inhibitor for the A16V+S108T Mutant of Dihydrofolate Reductase from the Cycloguanil-Resistant Strain (T9/94) of <i>Plasmodium falciparum</i>^†
  作者：Yongyuth Yuthavong、Tirayut Vilaivan、Netnapa Chareonsethakul、Sumalee Kamchonwongpaisan、Worachart Sirawaraporn、Rachel Quarrell、Gordon Lowe

  DOI：10.1021/jm0009181

  日期：2000.7.1

  The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dihydrofolate reductase (DHFR) is a key mutant responsible for cycloguanil-resistant malaria due to steric interaction between Val-16 and one of the C-2 methyl groups of cycloguanil. 4,6-Diamino-1,2-dihydrotriazines have been prepared, in which both methyl groups of cycloguanil are replaced by H or by H and an alkyl or phenyl group, and their inhibition constants against wild-type and mutant DHFR determined. The S108T mutation is considered to decrease cycloguanil binding further through the effect on the orientation of the p-chlorophenyl group. By moving the p-chloro-substituent to the m-position in the chlorophenyl group, the activity against the A16V+S108T mutant enzyme is improved, and this effect is reinforced by the p-chloro substituent in the 3,4-dichlorophenyl group. A lead compound has been found with inhibitory activity similar to that of cycloguanil against the wild-type DHFR and about 120-fold more effective than cycloguanil against the A16V+S108T mutant enzyme. The activity of this compound against P. falciparum clone (T9/94 RC17) which harbors the A16V+S108T DHFR is about 85-fold greater than cycloguanil.