4-chloro-2-methoxy-1-phenoxybenzene | 666750-28-3

• 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: 4-chloro-2-methoxy-1-phenoxybenzene
• CAS: 666750-28-3
• 化学式: C₁₃H₁₁ClO₂
• 分子量: 234.682
• InChiKey: MMVASWXLOMEZIZ-UHFFFAOYSA-N

物化性质

• 沸点：
  318.4±22.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  18.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-chloro-2-methoxy-1-phenoxybenzene 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以67%的产率得到5-Chlor-2-phenoxy-phenol
  参考文献：
  名称：

  Inhibition of the Bacterial Enoyl Reductase FabI by Triclosan:  A Structure−Reactivity Analysis of FabI Inhibition by Triclosan Analogues

  摘要：

  To explore the molecular basis for the picomolar affinity of triclosan for FabI, the enoyl reductase enzyme from the type II fatty acid biosynthesis pathway in Escherichia coli, an SAR study has been conducted using a series of triclosan analogues. Triclosan (1) is a slow, tight-binding inhibitor of FabI, interacting specifically with the E-NAD+ form of the enzyme with a K-1 value of 7 pM. In contrast, 2-phenoxyphenol (2) binds with equal affinity to the E.NAD+ (K-1 = 0.5 muM) and E.NADH (K-2 = 0.4 muM) forms of the enzyme and lacks the slow-binding step observed for triclosan. Thus, removal of the three triclosan chlorine atoms reduces the affinity of the inhibitor for FabI by 70 000-fold and removes the preference for the E.NAD+ FabI complex. 5-Chloro-2-phenoxyphenol (3) is a slow, tight-binding inhibitor of FabI and binds to the E.NAD+ form of the enzyme (K-1 = 1.1 pM) 7-fold more tightly than triclosan. Thus, while the two ring B chlorine atoms are not required for FabI inhibition, replacement of the ring A chlorine increases binding affinity by 450 000-fold. Given this remarkable observation, the SAR study was extended to the 5-fluoro-2-phenoxyphenol (4) and 5-methyl-2-phenoxyphenol (5) analogues to further explore the role of the ring A substituent. While both 4 and 5 are slow, tight-binding inhibitors, they bind substantially less tightly to FabI than triclosan. Compound 4 binds to both E.NAD+ and E.NADH forms of the enzyme with K-1 and K-2 values of 3.2 and 240 nM, respectively, whereas compound 5 binds exclusively to the E.NADH enzyme complex with a K-2 value of 7.2 nM. Thus, the ring A substituent is absolutely required for slow, tight-binding inhibition. In addition, pK(a) measurements coupled with simple electrostatic calculations suggest that the interaction of the ring A substituent with F203 is a major factor in governing the affinity of analogues 3-5 for the FabI complex containing the oxidized form of the cofactor.

  DOI：

  10.1021/jm030182i
• 作为产物：
  描述：

  碘苯 、 4-氯-2-甲氧基苯酚 在 copper(I) trifluoromethanesulfonate benzene 1-萘甲酸 、 caesium carbonate 作用下， 以 乙酸乙酯 、 甲苯 为溶剂， 生成 4-chloro-2-methoxy-1-phenoxybenzene
  参考文献：
  名称：

  Diphenyl ether antimicrobial compounds

  摘要：

  本发明涉及具有以下式的化合物：其中A1、A3、A6和A8独立地表示CH或N；A2表示N或C-X1a-R1；A4表示N或C-X2b-R2；R1和R2独立地表示H，或含有至少一个碳原子和最多二十六个碳原子的碳氢化合物，其中该碳氢化合物未经取代或用一种或多种-OH、NH2、SH、卤素或-COOH取代；X1和X2独立地表示-O-、-S-、-NH-、-C（O）O-、-C（O）-、-C（O）NH-或-SO2NH-；a和b独立地表示0或1，但当a和b都为0时，R1和R2不同时为H；当a为1时，R1不为H；当b为1时，R2不为H；A5和A9独立地表示CR3或N；R3表示H、甲基、乙基或卤素；A7表示CR4或N；R4表示H、甲基、乙基、卤素、硝基、羟基、氨基、酰胺基或用卤素、硝基、羟基、氨基或酰胺基取代的甲基或乙基基团；其中A2和A4不同时为N；且A5、A6、A7、A8和A9中不超过三个为N。本发明还涉及包含式（1）的化合物和药学上可接受的载体的制药组合物。本发明还涉及一种抑制哺乳动物中编码fabI基因、fabK基因、fabL基因或其组合的烯醇还原酶酶的细菌的生长的方法，该方法包括向哺乳动物中施加有效量的符合式（1）的化合物。

  公开号：

  US20060041025A1

文献信息

• Diphenyl ether antimicrobial compounds
  申请人：Tonge J. Peter

  公开号：US20060041025A1

  公开（公告）日：2006-02-23

  The present invention is directed to compounds having the formula: wherein A 1 , A 3 , A 6 , and A 8 independently represent CH or N; A 2 represents N or C—X 1 a —R 1 ; A 4 represents N or C—X 2 b —R 2 ; R 1 and R 2 independently represent H, or a hydrocarbon containing a minimum of one carbon atom and a maximum of twenty six carbon atoms, wherein the hydrocarbon is unsubstituted, or is substituted with one or more of —OH, —NH 2 , —SH, halo, or —COOH; X 1 and X 2 independently represent —O—, —S—, —NH—, —C(O)O—, —C(O)—, —C(O)NH—, or —SO 2 NH—; a and b independently represent 0 or 1, provided that when a and b are both 0, then R 1 and R 2 are not both H; when a is 1, then R 1 is not H; and when b is 1, then R 2 is not H; A 5 and A 9 independently represent CR 3 or N; R 3 represents H, methyl, ethyl, or halo; A 7 represents CR 4 or N; R 4 represents H, methyl, ethyl, halo, nitro, hydroxy, amino, amido, or a methyl or ethyl group substituted with halo, nitro, hydroxy, amino, or amido; provided that A 2 and A 4 are not both N; and not more than three of A 5 , A 6 , A 7 , A 8 , and A 9 are N. The invention is also directed to pharmaceutical compositions comprising a compound according to (1) and a pharmaceutically acceptable carrier. The invention is also directed to methods of inhibiting the growth of a bacterium containing an enoyl reductase enzyme encoded by a fabI gene, a fabK gene, a fabL gene, or a combination thereof, in a mammal in need thereof, the method comprising administering to the mammal an effective amount of a compound according to formula (1).

  本发明涉及具有以下式的化合物：其中A1、A3、A6和A8独立地表示CH或N；A2表示N或C-X1a-R1；A4表示N或C-X2b-R2；R1和R2独立地表示H，或含有至少一个碳原子和最多二十六个碳原子的碳氢化合物，其中该碳氢化合物未经取代或用一种或多种-OH、NH2、SH、卤素或-COOH取代；X1和X2独立地表示-O-、-S-、-NH-、-C（O）O-、-C（O）-、-C（O）NH-或-SO2NH-；a和b独立地表示0或1，但当a和b都为0时，R1和R2不同时为H；当a为1时，R1不为H；当b为1时，R2不为H；A5和A9独立地表示CR3或N；R3表示H、甲基、乙基或卤素；A7表示CR4或N；R4表示H、甲基、乙基、卤素、硝基、羟基、氨基、酰胺基或用卤素、硝基、羟基、氨基或酰胺基取代的甲基或乙基基团；其中A2和A4不同时为N；且A5、A6、A7、A8和A9中不超过三个为N。本发明还涉及包含式（1）的化合物和药学上可接受的载体的制药组合物。本发明还涉及一种抑制哺乳动物中编码fabI基因、fabK基因、fabL基因或其组合的烯醇还原酶酶的细菌的生长的方法，该方法包括向哺乳动物中施加有效量的符合式（1）的化合物。
• US7687547B2
  申请人：——

  公开号：US7687547B2

  公开（公告）日：2010-03-30
• [EN] DIPHENYL ETHER ANTIMICROBIAL COMPOUNDS<br/>[FR] COMPOSES ANTIMICROBIENS DE DIPHENYL ETHER
  申请人：UNIV NEW YORK STATE RES FOUND

  公开号：WO2006137840A2

  公开（公告）日：2006-12-28

  [EN] The present invention is directed to compounds having the formula: wherein A¹, A³, A⁶, and A⁸ independently represent CH or N; A² represents N or C-­X¹
  [FR] L'invention concerne des composés représentés par la formule (I), dans laquelle A¹, A³, A⁶, et A⁸ représentent de façon indépendante CH ou N; A² représente N ou C--X¹
• Inhibition of the Bacterial Enoyl Reductase FabI by Triclosan:  A Structure−Reactivity Analysis of FabI Inhibition by Triclosan Analogues
  作者：Sharada Sivaraman、Todd J. Sullivan、Francis Johnson、Polina Novichenok、Guanglei Cui、Carlos Simmerling、Peter J. Tonge

  DOI：10.1021/jm030182i

  日期：2004.1.1

  To explore the molecular basis for the picomolar affinity of triclosan for FabI, the enoyl reductase enzyme from the type II fatty acid biosynthesis pathway in Escherichia coli, an SAR study has been conducted using a series of triclosan analogues. Triclosan (1) is a slow, tight-binding inhibitor of FabI, interacting specifically with the E-NAD+ form of the enzyme with a K-1 value of 7 pM. In contrast, 2-phenoxyphenol (2) binds with equal affinity to the E.NAD+ (K-1 = 0.5 muM) and E.NADH (K-2 = 0.4 muM) forms of the enzyme and lacks the slow-binding step observed for triclosan. Thus, removal of the three triclosan chlorine atoms reduces the affinity of the inhibitor for FabI by 70 000-fold and removes the preference for the E.NAD+ FabI complex. 5-Chloro-2-phenoxyphenol (3) is a slow, tight-binding inhibitor of FabI and binds to the E.NAD+ form of the enzyme (K-1 = 1.1 pM) 7-fold more tightly than triclosan. Thus, while the two ring B chlorine atoms are not required for FabI inhibition, replacement of the ring A chlorine increases binding affinity by 450 000-fold. Given this remarkable observation, the SAR study was extended to the 5-fluoro-2-phenoxyphenol (4) and 5-methyl-2-phenoxyphenol (5) analogues to further explore the role of the ring A substituent. While both 4 and 5 are slow, tight-binding inhibitors, they bind substantially less tightly to FabI than triclosan. Compound 4 binds to both E.NAD+ and E.NADH forms of the enzyme with K-1 and K-2 values of 3.2 and 240 nM, respectively, whereas compound 5 binds exclusively to the E.NADH enzyme complex with a K-2 value of 7.2 nM. Thus, the ring A substituent is absolutely required for slow, tight-binding inhibition. In addition, pK(a) measurements coupled with simple electrostatic calculations suggest that the interaction of the ring A substituent with F203 is a major factor in governing the affinity of analogues 3-5 for the FabI complex containing the oxidized form of the cofactor.