N-nonyl-aminomethylene-1,1-bisphosphonate

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机膦酸及其衍生物
• 英文名称: N-nonyl-aminomethylene-1,1-bisphosphonate
• 英文别名: N-(n-nonyl)aminomethylenebisphosphonic acid；1-n-nonylaminomethyl-1,1-bisphosphonic acid；N-nonyl-aminomethylene-bisphosphonate；[(nonylamino)-phosphonomethyl]phosphonic acid
• 化学式: C₁₀H₂₅NO₆P₂
• 分子量: 317.259
• InChiKey: LACBURUYQJYAPW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.9
• 重原子数：
  19
• 可旋转键数：
  11
• 环数：
  0.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  127
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  壬胺 在 盐酸 作用下， 以 水 为溶剂， 反应 26.0h， 生成 N-nonyl-aminomethylene-1,1-bisphosphonate
  参考文献：
  名称：

  1-烷基氨基甲基-1,1-双膦酸的合成及其对克鲁氏锥虫和弓形虫的生物学评价。

  摘要：

  作为我们旨在寻找针对南美锥虫病和弓形虫病的新型化学治疗剂的项目的扩展，分别设计，合成了几种1,1-双膦酸酯，并分别针对这些疾病的病原体克氏锥虫和弓形体弓形虫进行了生物学评估。特别地，并且基于针对法呢基二磷酸合酶的2-烷基氨基乙基-1,1-双膦酸酯表现出的抗寄生虫活性，一系列的线性2-烷基氨基甲基-1,1-双膦酸（化合物21-33），即氨基的位置是一个更靠近宝石膦酸酯部分的碳原子，被评估为对克氏锥虫临床上更相关的分裂形式（amastigotes）的生长抑制剂。尽管所有这些化合物都没有抗寄生虫活性，这些结果对于严格的SAR研究是有价值的。另外，出乎意料的是，合成设计的2-环烷基氨基乙基-1，1-双膦酸47-49没有抗寄生虫活性。此外，长链含硫的1，1-双膦酸，例如化合物54-56、59，被证明是刚地弓形虫速殖子的纳摩尔生长抑制剂。由于许多含双膦酸酯的分子是FDA批准的用于治疗骨吸收疾病的药物，

  DOI：

  10.1016/j.bmc.2019.07.004

文献信息

• 3-D QSAR Investigations of the Inhibition of <i>Leishmania </i><i>m</i><i>ajor</i> Farnesyl Pyrophosphate Synthase by Bisphosphonates
  作者：John M. Sanders、Aurora Ortiz Gómez、Junhong Mao、Gary A. Meints、Erin M. Van Brussel、Agnieszka Burzynska、Pawel Kafarski、Dolores González-Pacanowska、Eric Oldfield

  DOI：10.1021/jm0302344

  日期：2003.11.1

  set results (N = 62 compounds) yielded good correlations with each technique (R(2) = 0.87 and 0.88, respectively), and were further validated by using a training/test set approach. Test set results (N = 24 compounds) indicated that IC(50) values could be predicted within factors of 2.9 and 2.7 for the CoMFA and CoMSIA methods, respectively. The CoMSIA fields indicated that a positive charge in the bisphosphonate

  我们报告了作为利什曼原虫主要甲羟戊酸/异戊二烯生物合成途径酶，法呢基焦磷酸合酶的抑制剂的62二膦酸盐的活性。所研究的化合物具有约100 nM至约80 microM（相当于K（i）值低至10 nM）的活性（IC（50）值）。发现活性最高的化合物是唑来膦酸盐（据报道其单晶X射线结构），吡啶基-乙烷-1-羟基-1,1-双膦酸酯或吡啶甲基氨基亚甲基双膦酸酯。但是，N-脂环族氨基亚甲基双膦酸酯（如茚满膦酸酯）（N-环庚基氨基亚甲基双膦酸酯）以及含有短（n = 4、5）烷基链的脂族氨基亚甲基双膦酸酯也具有活性，IC（50）值在200-1700 nM范围内（对应于大约20-170 nM的K（i）值）。含有更长或多个（N，N-）烷基取代基的双膦酸酯是无活性的，环上缺少邻或间氮原子或具有多个卤素取代基或对氨基的芳香族化合物也是如此。为了将这些观察结果放在更定量的结构基础上，我们使用了三维定量结构-活性关系技
• Effects of Bisphosphonates on the Growth of <i>Entamoeba histolytica</i> and <i>Plasmodium </i>Species in Vitro and in Vivo
  作者：Subhash Ghosh、Julian M. W. Chan、Christopher R. Lea、Gary A. Meints、Jared C. Lewis、Zev S. Tovian、Ryan M. Flessner、Timothy C. Loftus、Iris Bruchhaus、Howard Kendrick、Simon L. Croft、Robert G. Kemp、Seiki Kobayashi、Tomoyoshi Nozaki、Eric Oldfield

  DOI：10.1021/jm030084x

  日期：2004.1.1

  The effects of a series of 102 bisphosphonates on the inhibition of growth of Entamoeba histolytica and Plasmodium falciparum in vitro have been determined, and selected compounds were further investigated for their in vivo activity. Forty-seven compounds tested were active (IC50 < 200 muM) versus E. histolytica growth in vitro. The most active compounds (IC50 similar to 4-9 muM) were nitrogen-containing bisphosphonates with relatively large aromatic side chains. Simple n-alkyl-1-hydroxy-1,1-bisphosphonates, known inhibitors of the enzyme farnesylpyrophosphate (FPP) synthase, were also active, with optimal activity being found with C9-C10 side chains. However, numerous other nitrogen-containing bisphosphonates known to be potent FPP synthase inhibitors, such as risedronate or pamidronate, had little or no activity. Several pyridine-derived bisphosphonates were quite active (IC50 similar to 10-20 muM), and this activity was shown to correlate with the basicity of the aromatic group, with activity decreasing with increasing pK(a) values. The activities of all compounds were tested versus a human nasopharyngeal carcinoma (KB) cell line to enable an estimate of the therapeutic index (TI). Five bisphosphonates were selected and then screened for their ability to delay the development of amebic liver abscess formation in an E. histolytica infected hamster model. Two compounds were found to decrease liver abscess formation at 10 mg/kg ip with little or no effect on normal liver mass. With P. falciparum, 35 compounds had IC50 values <200 muM in an in vitro assay. The most active compounds were also simple n-alkyl-1-hydroxy-1,1-bisphosphonates, having IC50 values around 1 muM. Five compounds were again selected for in vivo investigation in a Plasmodium berghei ANKA BALB/c mouse suppressive test. The most active compound, a C9 n-alkyl side chain containing bisphosphonate, caused an 80% reduction in parasitemia with no overt toxicity. Taken together, these results show that bisphosphonates appear to be useful lead compounds for the development of novel antiamebic and antimalarial drugs.
• Synthesis and biological evaluation of 1-alkylaminomethyl-1,1-bisphosphonic acids against Trypanosoma cruzi and Toxoplasma gondii
  作者：Tamila Galaka、Bruno N. Falcone、Catherine Li、Sergio H. Szajnman、Silvia N.J. Moreno、Roberto Docampo、Juan B. Rodriguez

  DOI：10.1016/j.bmc.2019.07.004

  日期：2019.8

  of our project aimed at the search for new chemotherapeutic agents against Chagas disease and toxoplasmosis, several 1,1-bisphosphonates were designed, synthesized and biologically evaluated against Trypanosoma cruzi and Toxoplasma gondii, the etiologic agents of these diseases, respectively. In particular, and based on the antiparasitic activity exhibited by 2-alkylaminoethyl-1,1-bisphosphonates targeting

  作为我们旨在寻找针对南美锥虫病和弓形虫病的新型化学治疗剂的项目的扩展，分别设计，合成了几种1,1-双膦酸酯，并分别针对这些疾病的病原体克氏锥虫和弓形体弓形虫进行了生物学评估。特别地，并且基于针对法呢基二磷酸合酶的2-烷基氨基乙基-1,1-双膦酸酯表现出的抗寄生虫活性，一系列的线性2-烷基氨基甲基-1,1-双膦酸（化合物21-33），即氨基的位置是一个更靠近宝石膦酸酯部分的碳原子，被评估为对克氏锥虫临床上更相关的分裂形式（amastigotes）的生长抑制剂。尽管所有这些化合物都没有抗寄生虫活性，这些结果对于严格的SAR研究是有价值的。另外，出乎意料的是，合成设计的2-环烷基氨基乙基-1，1-双膦酸47-49没有抗寄生虫活性。此外，长链含硫的1，1-双膦酸，例如化合物54-56、59，被证明是刚地弓形虫速殖子的纳摩尔生长抑制剂。由于许多含双膦酸酯的分子是FDA批准的用于治疗骨吸收疾病的药物，