5-{[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}biphenyl-2-carboxylic acid | 489409-15-6

• 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: 5-{[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}biphenyl-2-carboxylic acid
• 英文别名: 4-[[3-[(4-Cyanophenyl)methyl]imidazol-4-yl]methylamino]-2-phenylbenzoic acid
• CAS: 489409-15-6
• 化学式: C₂₅H₂₀N₄O₂
• 分子量: 408.459
• InChiKey: KQTRQKZXLWEXSG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  90.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-{[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}biphenyl-2-carboxylic acid 在 lithium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 FTI-2289
  参考文献：
  名称：

  Design and Synthesis of Peptidomimetic Protein Farnesyltransferase Inhibitors as Anti-Trypanosoma brucei Agents

  摘要：

  On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucel protein farnesyltransferase (TbPFT) was evaluated. Peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nM in the enzyme assay, whereas the corresponding C-4 regioisomers were less potent. The ester prodrug 23 was found to be a potent inhibitor against cultured Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense cells with ED50 values of 0.025 and 0.0026 muM, respectively. Furthermore introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED50 of 0.0015 muM. The potency of the TbPFT inhibitors and the cytotoxicity of the corresponding esters to T. brucei cells were shown to be highly correlated. These studies validate TbPFT as a target for the development of novel therapeutics against African sleeping sickness.

  DOI：

  10.1021/jm030236o
• 作为产物：
  描述：

  4-硝基-2-苯基苯甲酸 在 palladium on activated charcoal 氯化亚砜 、 氢气 、 四氯化钛 、 sodium cyanoborohydride 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 5-{[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}biphenyl-2-carboxylic acid
  参考文献：
  名称：

  Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity

  摘要：

  Malaria continues to represent a very serious health problem in the tropics. The current methods of clinical treatment are showing deficiencies due to the increased incidence of resistance in the parasite. In the present paper we report the design, synthesis, and evaluation of potential antimalarial agents against a novel target, protein farnesyltransferase. We show that the most potent compounds are active against Plasmodium falciparum in vitro at submicromolar concentrations. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00055-5

文献信息

• Compounds and methods for the inhibition of compounds cruzi
  申请人：Hamilton D Andrew

  公开号：US20060167269A1

  公开（公告）日：2006-07-27

  The present invention relates to compounds according to the formula (I): Where R A is a C 1 -C 10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group according to the formula (II): R B is a C 1 -C 10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group of the formula (III): R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from H, C 1 -C 10 (preferably a C 1 -C 4 ) alkyl or alkenyl group, CF 3 , F, Cl, Br, I, CN, NO 2 , NH 2 , NHR, NRR, COR (acyl group), OR (hydroxyl or ether group), CO 2 R (carboxylic acid or ester group), or COSR (thioester group) where R is H or a C 1 -C 10 (preferably a C 1 -C 4 ) alkyl or alkenyl group, an unsubstituted or substituted aryl (preferably, phenyl) or heterocycle group, or a (IV) group, where R 3 is H, a C 1 -C 10 (preferably a C 1 -C 4 ) alkyl, alkenyl, ether or a thioether group; and R 11 and R 12 are independently selected from H or a C 1 -C 3 alkyl or alkenyl group, or a pharmaceutically acceptable salt thereof and methods for treating infections caused by protozoal, fungal and/or bacterial agents such as Trypanosoma cruzi, Mycobacterium spp., Leishmania spp., Cryptococcus spp., Aspergillus spp., Histoplasma spp., Candida spp., especially Candida albicans, Pneumocystis carinii, Trichophyton spp., Microsporum spp., Malassezia spp., Rhizopus spp., Pseudallescheria spp., Blastomyces dermatitidis and Coccidiodes spp., among others.

  本发明涉及式(I)的化合物：其中RA是C1-C10取代或未取代的线性、支链或环烷基或烯基或式(II)的苯基：RB是C1-C10取代或未取代的线性、支链或环烷基或烯基或式(III)的苯基：R1、R2、R3、R4、R5、R6、R7、R8、R9和R10各自独立地选自H、C1-C10(优选为C1-C4)烷基或烯基、CF3、F、Cl、Br、I、CN、NO2、NH2、NHR、NRR、COR（酰基）、OR（羟基或醚基）、CO2R（羧酸或酯基）或COSR（硫酯基），其中R是H或C1-C10(优选为C1-C4)烷基或烯基、未取代或取代的芳基（优选为苯基）或杂环基，或式(IV)的基团，其中R3是H、C1-C10(优选为C1-C4)烷基、烯基、醚或硫醚基；R11和R12各自独立地选自H或C1-C3烷基或烯基，或其药学上可接受的盐，以及用于治疗由原虫、真菌和/或细菌引起的感染的方法，例如Trypanosoma cruzi，Mycobacterium spp.，Leishmania spp.，Cryptococcus spp.，Aspergillus spp.，Histoplasma spp.，Candida spp.，特别是Candida albicans，Pneumocystis carinii，Trichophyton spp.，Microsporum spp.，Malassezia spp.，Rhizopus spp.，Pseudallescheria spp.，Blastomyces dermatitidis和Coccidioides spp.等。
• [EN] COMPOUNDS AND METHODS FOR THE INHIBITION OF TRYPANOSOMA CRUZ I<br/>[FR] COMPOSES ET PROCEDES D'INHIBITION DE TRYPANOSOMA CRUZI
  申请人：UNIV YALE

  公开号：WO2003006012A1

  公开（公告）日：2003-01-23

  The present invention relates to compounds according to the formula (I): Where RA is a C¿1?-C10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group according to the formula (II): R?B¿ is a C¿1?-C10 substituted or unsubstituted linear, branch-chained or cyclic alkyl or alkenyl group or a phenyl group of the formula (III): R?1, R2 , R3, R4, R5, R6, R7, R8, R9 and R10¿ are each independently selected from H, C¿1?-C10(preferably a C1-C4)alkyl or alkenyl group, CF3, F, Cl, Br, I, CN, NO2, NH2, NHR, NRR, COR (acyl group), OR (hydroxyl or ether group), CO2R (carboxylic acid or ester group ), or COSR (thioester group) where R is H or a C1-C10(preferably a C1-C4)alkyl or alkenyl group, an unsubstituted or substituted aryl (preferably, phenyl) or heterocycle group, or a (IV) group, where R3 is H, a C1-C10 (preferably a C1-C4) alkyl, alkenyl, ether or a thioether group; and R?11 and R12¿ are independently selected from H or a C¿1?-C3 alkyl or alkenyl group, or a pharmaceutically acceptable salt thereof and methods for treating infections caused by protozoal, fungal and/or bacterial agents such as Trypanosoma cruzi, Mycobacterium spp., Leishmania spp., Cryptococcus spp., Aspergillus spp., Histoplasma spp., Candida spp. especially Candida albicans, Pneumocystis carinii, Trichophyton spp., Microsporum spp., Malassezia spp., Rhizopus spp., Pseudallescheria spp., Blastomyces dermatitidis and Coccidiodes spp., among others.
• Design and Synthesis of Peptidomimetic Protein Farnesyltransferase Inhibitors as Anti-<i>Trypanosoma brucei </i>Agents
  作者：Junko Ohkanda、Frederick S. Buckner、Jeffrey W. Lockman、Kohei Yokoyama、Dora Carrico、Richard Eastman、Kate de Luca-Fradley、Wendy Davies、Simon L. Croft、Wesley C. Van Voorhis、Michael H. Gelb、Saïd M. Sebti、Andrew D. Hamilton

  DOI：10.1021/jm030236o

  日期：2004.1.1

  On the basis of the structure of the CVIM tetrapeptide substrate of mammalian protein farnesyltransferase, a series of imidazole-containing peptidomimetics was designed and synthesized, and their inhibition activity against Trypanosoma brucel protein farnesyltransferase (TbPFT) was evaluated. Peptidomimetics where the 5-position of the imidazole ring was linked to the hydrophobic scaffold showed over 70% inhibition activity at 50 nM in the enzyme assay, whereas the corresponding C-4 regioisomers were less potent. The ester prodrug 23 was found to be a potent inhibitor against cultured Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense cells with ED50 values of 0.025 and 0.0026 muM, respectively. Furthermore introducing a second imidazole group into 23 led to 31, which showed the highest inhibition activity against the parasite with an ED50 of 0.0015 muM. The potency of the TbPFT inhibitors and the cytotoxicity of the corresponding esters to T. brucei cells were shown to be highly correlated. These studies validate TbPFT as a target for the development of novel therapeutics against African sleeping sickness.
• Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity
  作者：Junko Ohkanda、Jeffrey W. Lockman、Kohei Yokoyama、Michael H. Gelb、Simon L. Croft、Howard Kendrick、Maria Isabel Harrell、Jean E. Feagin、Michelle A. Blaskovich、Said M. Sebti、Andrew D. Hamilton

  DOI：10.1016/s0960-894x(01)00055-5

  日期：2001.3

  Malaria continues to represent a very serious health problem in the tropics. The current methods of clinical treatment are showing deficiencies due to the increased incidence of resistance in the parasite. In the present paper we report the design, synthesis, and evaluation of potential antimalarial agents against a novel target, protein farnesyltransferase. We show that the most potent compounds are active against Plasmodium falciparum in vitro at submicromolar concentrations. (C) 2001 Elsevier Science Ltd. All rights reserved.