7β-amino-3-[3-formamido-4-(formamidomethyl)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate bis(trifluoroacetate) | 1025391-94-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 7β-amino-3-[3-formamido-4-(formamidomethyl)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate bis(trifluoroacetate)
• CAS: 1025391-94-9
• 化学式: C₂F₃O₂*C₂HF₃O₂*C₁₅H₁₉N₆O₅S
• 分子量: 622.459
• InChiKey: INSSXPMMRIKDFV-FMJMIDLFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.36
• 重原子数：
  41.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  228.07
• 氢给体数：
  5.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-[(1-tert-butoxycarbonyl-1-methylethoxy)imino]acetyl chloride hydrochloride 、 7β-amino-3-[3-formamido-4-(formamidomethyl)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate bis(trifluoroacetate) 在 N-三甲基硅基乙酰胺 、 苯甲醚 、 三氟乙酸 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 二氯甲烷 为溶剂， 反应 2.0h， 生成 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-formamido-4-(formamidomethyl)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate bis(trifluoroacetate)
  参考文献：
  名称：

  Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure

  摘要：

  AmpC beta-lactamase is one of the leading causes of Pseudomonas aeruginosa (P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC = 1 mu g/mL) against the AmpC beta-lactamase overproducing P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 454; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 455; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 456; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 457] (MIC = 16 mu g/mL) and ceftazidime (CAZ) (MIC = 128 mu g/mL). The stability of FR259647 and FK518 to AmpC beta-lactamase was evaluated using MIC assays against both the P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC beta-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC beta-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives 4-9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.074
• 作为产物：
  描述：

  5-(formylamino)-4-(formylaminomethyl)-1-methylpyrazole 、 7Β-叔丁氧羰基氨基-3-氯甲基-3-头孢烯-4-羧酸二苯甲酯 、 三氟乙酸 在 sodium iodide 、 苯甲醚 作用下， 以 N,N-二甲基甲酰胺 、 二氯甲烷 为溶剂， 反应 32.0h， 生成 7β-amino-3-[3-formamido-4-(formamidomethyl)-2-methyl-1-pyrazolio]methyl-3-cephem-4-carboxylate bis(trifluoroacetate)
  参考文献：
  名称：

  Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure

  摘要：

  AmpC beta-lactamase is one of the leading causes of Pseudomonas aeruginosa (P. aeruginosa) resistance to cephalosporins. FR259647 is a cephalosporin having a novel pyrazolium substituent at the 3-position and exhibits excellent activity (MIC = 1 mu g/mL) against the AmpC beta-lactamase overproducing P. aeruginosa FP1380 strain in comparison with the third-generation cephalosporins FK518 [Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 454; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 455; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 456; Abstracts of Papers, 30th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, GA, October 21-24, 1990, Abs. 457] (MIC = 16 mu g/mL) and ceftazidime (CAZ) (MIC = 128 mu g/mL). The stability of FR259647 and FK518 to AmpC beta-lactamase was evaluated using MIC assays against both the P. aeruginosa PAO1 strain and a PAO1 mutant strain overproducing AmpC beta-lactamase as a differential assay, which indicates that the main difference derives from their stability to AmpC beta-lactamase. A structural analysis using computer simulations indicated that the difference in stability may be due to steric hindrance of the 3-position substituents causing differential affinity. This steric hindrance may disturb entry of the cephalosporins into the binding pocket. We predicted the possibility of inhibition of entry as a potential means of enhancing stability by conformational analysis. In order to validate this speculation, novel FR259647 derivatives 4-9 were designed, calculated, synthesized, and evaluated. As a result, we demonstrated that their probability of entry correlated with the MIC ratio of the mutant strain to the parent strain and supports the validity of our model. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.11.074