6-(naphthalen-1-ylamino-methyl)-pteridine-2,4-diamine | 70583-39-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: 6-(naphthalen-1-ylamino-methyl)-pteridine-2,4-diamine
• 英文别名: 2,4-Pteridinediamine, 6-((1-naphthalenylamino)-methyl)-；6-[(naphthalen-1-ylamino)methyl]pteridine-2,4-diamine
• CAS: 70583-39-0
• 化学式: C₁₇H₁₅N₇
• 分子量: 317.353
• InChiKey: QVHFSGMRVQZGMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-(溴甲基)-2,4-蝶啶二胺 、 1-萘胺 生成 6-(naphthalen-1-ylamino-methyl)-pteridine-2,4-diamine
  参考文献：
  名称：

  Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against Toxoplasma gondii and Pneumocystis carinii in in Vitro Evaluations

  摘要：

  2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-dieazapteridines and four 2,4-diaminoquinazolines, each with an aryl group attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3), CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 mu M) with 14 compounds below 0.1 mu M, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 mu M). As inhibitors of T. gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 mu M) and trimetrexate (0.010 mu M), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 mu M) and trimetrexate (0.042 mu M). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 mu M or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose B-substituent is CH2CH2C6H3(OCH3)(2)-2,5. This compound is over 10(3)-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)(2)-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.

  DOI：

  10.1021/jm950760y

文献信息

• Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1
  作者：Ina Pöhner、Antonio Quotadamo、Joanna Panecka-Hofman、Rosaria Luciani、Matteo Santucci、Pasquale Linciano、Giacomo Landi、Flavio Di Pisa、Lucia Dello Iacono、Cecilia Pozzi、Stefano Mangani、Sheraz Gul、Gesa Witt、Bernhard Ellinger、Maria Kuzikov、Nuno Santarem、Anabela Cordeiro-da-Silva、Maria P. Costi、Alberto Venturelli、Rebecca C. Wade

  DOI：10.1021/acs.jmedchem.2c00232

  日期：2022.7.14

  antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure–activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective

  具有多个目标的化合物的优化是药物发现周期中一个困难的多维问题。在这里，我们提出了一种系统的、多学科的方法来开发选择性抗寄生虫化合物。新型蝶啶衍生物的基于计算片段的设计以及晶体结构确定的迭代允许推导多靶点抑制的结构-活性关系。该方法产生的化合物显示出对布氏蝶啶还原酶 1 (PTR1) 的明显皮摩尔抑制，对L. major的纳摩尔抑制PTR1，以及对寄生虫二氢叶酸还原酶 (DHFR) 与人类 DHFR 的选择性亚微摩尔抑制。此外，通过将多药理学设计与基于特性的寄生虫优化相结合，我们发现三种化合物对布氏布氏锥虫表现出微摩尔 EC 50值，同时保持其目标抑制作用。我们的结果为进一步开发基于蝶啶的化合物提供了基础，我们希望我们的多靶点方法普遍适用于抗感染药物的设计和优化。
• MONTGOMERY J. A.; PIPER J. R.; ELLIOTT R. D.; ROBERTS E. C.; TEMPLE C.; S+, J. HETEROCYCL. CHEM., 1979, 16, NO 3, 537-539
  作者：MONTGOMERY J. A.、 PIPER J. R.、 ELLIOTT R. D.、 ROBERTS E. C.、 TEMPLE C.、 S+

  DOI：——

  日期：——