1-(1-(sec-butyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethanone

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(1-(sec-butyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethanone
• 英文别名: 1-[1-(butan-2-yl)-1H-pyrazol-4-yl]-2,2,2-trifluoroethan-1-one；1-(1-butan-2-ylpyrazol-4-yl)-2,2,2-trifluoroethanone
• 化学式: C₉H₁₁F₃N₂O
• 分子量: 220.194
• InChiKey: GIGJIIJGHXYZQW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  34.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  三氟乙酸甲酯 、 4-bromo-1-(butan-2-yl)-1H-pyrazole 在 正丁基锂 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 2.0h， 以67%的产率得到1-(1-(sec-butyl)-1H-pyrazol-4-yl)-2,2,2-trifluoroethanone
  参考文献：
  名称：

  Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase

  摘要：

  Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored alpha-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 +/- 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.09.019

文献信息

• Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase
  作者：Eugene Camerino、Dawn M. Wong、Fan Tong、Florian Körber、Aaron D. Gross、Rafique Islam、Elisabet Viayna、James M. Mutunga、Jianyong Li、Maxim M. Totrov、Jeffrey R. Bloomquist、Paul R. Carlier

  DOI：10.1016/j.bmcl.2015.09.019

  日期：2015.10

  Malaria is a devastating disease in sub-Saharan Africa, and current vector control measures are threatened by emerging resistance mechanisms. With the goal of developing new, selective, resistance-breaking insecticides we explored alpha-fluorinated methyl ketones as reversible covalent inhibitors of Anopheles gambiae acetylcholinesterase (AgAChE). Trifluoromethyl ketones 5 demonstrated remarkable volatility in microtiter plate assays, but 5c,e-h exhibited potent (1-100 nM) inhibition of wild type (WT) AgAChE and weak inhibition of resistant mutant G119S mutant AgAChE. Fluoromethyl ketones 10c-i exhibited submicromolar to micromolar inhibition of WT AgAChE, but again only weakly inhibited G119S AgAChE. Interestingly, difluoromethyl ketone inhibitors 9c and 9g had single digit nanomolar inhibition of WT AgAChE, and 9g had excellent potency against G119S AgAChE. Approach to steady-state inhibition was quite slow, but after 23 h incubation an IC50 value of 25.1 +/- 1.2 nM was measured. We attribute the slow, tight-binding G119S AgAChE inhibition of 9g to a balance of steric size and electrophilicity. However, toxicities of 5g, 9g, and 10g to adult A. gambiae in tarsal contact, fumigation, and injection assays were lower than expected based on WT AgAChE inhibition potency and volatility. Potential toxicity-limiting factors are discussed. (C) 2015 Elsevier Ltd. All rights reserved.