2-(1-naphthyl)-1-hydroxyethane-1,1-diphosphonic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-(1-naphthyl)-1-hydroxyethane-1,1-diphosphonic acid
• 英文别名: [1-Hydroxy-2-(1-naphthyl)-1-phosphono-ethyl]phosphonic acid；(1-hydroxy-2-naphthalen-1-yl-1-phosphonoethyl)phosphonic acid
• 化学式: C₁₂H₁₄O₇P₂
• 分子量: 332.186
• InChiKey: BNXBJUGVJRQKSF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  135
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-萘乙酸 在 草酰氯 、 三(三甲代甲硅烷基)亚磷酸盐 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 苯 为溶剂， 反应 3.0h， 生成 2-(1-naphthyl)-1-hydroxyethane-1,1-diphosphonic acid
  参考文献：
  名称：

  Bisphosphonate Inhibition of the Exopolyphosphatase Activity of the Trypanosoma brucei Soluble Vacuolar Pyrophosphatase

  摘要：

  Trypanosoma brucei, the causative agent of African trypanosomiasis, contains a soluble, vacuolar pyrophosphatase, TbVSP1, not present in humans, which is essential for the growth of bloodstream forms in their mammalian host. Here, we report the inhibition of a recombinant TbVSP1 expressed in Escherichia coli by a panel of 81 bisphosphonates. The IC50 values were found to vary from similar to 2 to 850 mu M. We then used 3D QSAR (comparative molecular field and comparative molecular similarity index; CoMFA and CoMSIA) methods to analyze the enzyme inhibition results. The R-2 values for the experimental versus the QSAR-predicted activities were 0.78 or 0.61 for CoMFA and 0.79 or 0.68 for CoMSIA, for two different alignments. The root-mean-square (rms) pIC(50) error for the best CoMFA model was 0.41 for five test sets of five activity predictions, which translates to a factor of similar to 2.6 error in IC50 prediction. For CoMSIA, the rms pIC(50) error and error factors were 0.35 and 2.2, respectively. In general, the most active compounds contained both a single aromatic ring and a hydrogen bond donor feature. Thirteen of the more potent compounds were then tested in vivo in a mouse model of T. brucei infection. The most active compound in vivo provided a 40% protection from death with no apparent side effects, suggesting that further development of such compounds may be of interest.

  DOI：

  10.1021/jm058220g

文献信息

• Diphosphonsäure-Derivate und diese enthaltende pharmazeutische Präparate
  申请人：SCHERING AKTIENGESELLSCHAFT

  公开号：EP0085321A2

  公开（公告）日：1983-08-10

  Diphosphonsäure-Derivate der allgemeinen Formel I worin n die Ziffern 0, 1 oder 2 bedeuten und worin R, ein Wasserstoffatom oder eine 1 bis 4 Kohlenstoffatome enthaltende Alkylgruppe R2 ein Wasserstoffatom, ein Alkalimetallatom, ein Erdalkalimetallatom oder eine 1 bis 4 Kohlenstoffatome enthaltende Alkylgruppe und Ar einen gegebenenfalls durch Fluoratome, Chloratome, 1 bis 4 Kohlenstoffatome enthaltende Alkylgruppen oder 1 bis 4 Kohlenstoffatome enthaltende Alkoxygruppen substituierten Phenylrest, einen Naphthylrest, einen Biphenylrest oder einen Thienylrest darstellen, sind pharmakologisch wirksame Substanzen.

  通式 I 的二膦酸衍生物 其中 n 是数字 0、1 或 2，其中 R 是氢原子或含有 1 至 4 个碳原子的烷基 R2 代表氢原子、碱金属原子、碱土金属原子或含 1 至 4 个碳原子的烷基，Ar 代表可选被氟原子、氯原子、含 1 至 4 个碳原子的烷基或含 1 至 4 个碳原子的烷氧基、萘基、联苯基或噻吩基取代的苯基。
• Bisphosphonate Inhibition of the Exopolyphosphatase Activity of the <i>Trypanosoma brucei</i> Soluble Vacuolar Pyrophosphatase
  作者：Evangelia Kotsikorou、Yongcheng Song、Julian M. W. Chan、Stephanie Faelens、Zev Tovian、Erin Broderick、Norbert Bakalara、Roberto Docampo、Eric Oldfield

  DOI：10.1021/jm058220g

  日期：2005.9.1

  Trypanosoma brucei, the causative agent of African trypanosomiasis, contains a soluble, vacuolar pyrophosphatase, TbVSP1, not present in humans, which is essential for the growth of bloodstream forms in their mammalian host. Here, we report the inhibition of a recombinant TbVSP1 expressed in Escherichia coli by a panel of 81 bisphosphonates. The IC50 values were found to vary from similar to 2 to 850 mu M. We then used 3D QSAR (comparative molecular field and comparative molecular similarity index; CoMFA and CoMSIA) methods to analyze the enzyme inhibition results. The R-2 values for the experimental versus the QSAR-predicted activities were 0.78 or 0.61 for CoMFA and 0.79 or 0.68 for CoMSIA, for two different alignments. The root-mean-square (rms) pIC(50) error for the best CoMFA model was 0.41 for five test sets of five activity predictions, which translates to a factor of similar to 2.6 error in IC50 prediction. For CoMSIA, the rms pIC(50) error and error factors were 0.35 and 2.2, respectively. In general, the most active compounds contained both a single aromatic ring and a hydrogen bond donor feature. Thirteen of the more potent compounds were then tested in vivo in a mouse model of T. brucei infection. The most active compound in vivo provided a 40% protection from death with no apparent side effects, suggesting that further development of such compounds may be of interest.
• US4473560A
  申请人：——

  公开号：US4473560A

  公开（公告）日：1984-09-25
• Bisphosphonate Inhibitors of <i>Toxoplasma </i><i>g</i><i>ondi </i>Growth:  In Vitro<i>,</i> QSAR, and In Vivo Investigations
  作者：Yan Ling、Gurmukh Sahota、Sarah Odeh、Julian M. W. Chan、Fausto G. Araujo、Silvia N. J. Moreno、Eric Oldfield

  DOI：10.1021/jm040132t

  日期：2005.5.1

  We have investigated the activity of 60 bisphosphonates against the replication of Toxoplasma gondii in vitro and of three of the most active compounds, in vivo. The two most active compounds found were n-alkyl bisphosphonates containing long (n = 9 or 10) hydrocarbon chains, not the nitrogen-containing species used in bone resorption therapy. The target of all of the most active bisphosphonates appears to be the isoprene biosynthesis pathway enzyme farnesyl pyrophosphate synthase (FPPS), as indicated by the correlations between T. gondii growth inhibition and FPPS (human and Leishmania major) enzyme inhibition and by the fact that a T. gondii. strain engineered to overexpress FPPS required considerably higher levels of bisphosphonates to achieve 50% growth inhibition, while the IC50 for atovaquone (which does not inhibit FPPS) remained the same in the overexpressing strain. The phosphonate inhibitor of the non-mevalonate pathway, fosmidomycin, which inhibits the enzyme 1-deoxy-xylulose-5-phosphate reductoisomerase, had no effect on T. gondii growth. To investigate structure-activity relationships (SARs) in more detail, we used two three-dimensional quantitative SAR methods: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), to investigate all 60 bisphosphonates. Both the CoMFA and CoMSIA models indicated a 60-70% contribution from steric interactions and a 30-40% contribution from electrostatic interactions and using four N = 55 training sets for each method, we found on average between a factor of 2 and 3 error in IC50 prediction. The three most active compounds found in vitro were tested in vivo in a Smith-Webster mouse model and the two most active bisphosphonates were found to provide up to an 80% protection from death, a considerable improvement over that found previously with nitrogen-containing bisphosphonates. This effect may originate in the much higher therapeutic indices of these alkyl bisphosphonates, as deduced from in vitro assays using LD50 values for growth inhibition of a human cell line. Overall, these results indicate that alkyl bisphosphonates are promising compounds for further development as agents against Toxoplasma gondii growth, in vivo.