benzhydryl (2R,6R,7R)-7-(((allyloxy)carbonyl)amino)-3-(2-chloroacetoxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate | 1204431-35-5

• 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: benzhydryl (2R,6R,7R)-7-(((allyloxy)carbonyl)amino)-3-(2-chloroacetoxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate
• CAS: 1204431-35-5
• 化学式: C₂₇H₂₇ClN₂O₇S
• 分子量: 559.04
• InChiKey: WWSJTLKQIRDEGY-WJHUMLNOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.42
• 重原子数：
  38.0
• 可旋转键数：
  9.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  111.24
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为产物：
  描述：

  benzhydryl 6-(allyloxycarbonylamino)penicillinate-1-oxide 在 silver(I) acetate 、 magnesium sulfate 作用下， 以 1,4-二氧六环 、 乙酸乙酯 为溶剂， 反应 14.0h， 生成 benzhydryl 6-(Allyloxycarbonylamino)-2'β-(chloroacetoxy)penicillinate 、 benzhydryl (2R,6R,7R)-7-(((allyloxy)carbonyl)amino)-3-(2-chloroacetoxy)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]octane-2-carboxylate
  参考文献：
  名称：

  6-Arylmethylidene Penicillin-Based Sulfone Inhibitors for Repurposing Antibiotic Efficiency in Priority Pathogens

  摘要：

  The ability of 6-(aryl)methylidene penicillin-based sulfones 1-7 to repurpose beta-lactam antibiotics activity with bacterial species that carry carbapenem-hydrolyzing class D beta-lactamases (OXA-23, OXA-24/40 and OXA-48), as well as with class A (TEM-1, CTX-M-2) and class C (CMY-2, DHA-1) enzymes, is reported. The combinations imipenem/3 and imipenem/4 restored almost completely the antibiotic efficacy in OXA-23 and OXA-24/40 carbapenemase-producing A. baumannii strains (1 mu g mL(-1)) and also provided good results for OXA-48 carbapenemase-producing K. pneumoniae strains (4 mu g mL(-1)). Compounds 2-6 in combinations with ceftazidime and ampicillin were also efficient in restoring antibiotic efficacy in E. coli strains carrying class C (CMY-2 and DHA-1) and class A (TEM-1 and CTX-M-2) beta-lactamase enzymes, respectively. Kinetic and inhibition studies with the OXA-24/40 enzyme, protein mass spectrometry analysis and docking studies allowed us to gain an insight into the inhibition mechanism and the experimentally observed differences between the ligands.

  DOI：

  10.1021/acs.jmedchem.0c00127

文献信息

• Design, Synthesis, and Crystal Structures of 6-Alkylidene-2′-Substituted Penicillanic Acid Sulfones as Potent Inhibitors of <i>Acinetobacter baumannii</i> OXA-24 Carbapenemase
  作者：German Bou、Elena Santillana、Anjaneyulu Sheri、Alejandro Beceiro、Jared M. Sampson、Matthew Kalp、Christopher R. Bethel、Anne M. Distler、Sarah M. Drawz、Sundar Ram Reddy Pagadala、Focco van den Akker、Robert A. Bonomo、Antonio Romero、John D. Buynak

  DOI：10.1021/ja104092z

  日期：2010.9.29

  enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel β-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2'-substituted penicillanic acid sulfones (1-5) were synthesized and tested against OXA-24, a clinically important β-lactamase that inactivates carbapenems and is found in A. baumannii. Based upon the roles Tyr112 and Met223 play

  D 类 β-内酰胺酶代表了一类不断增长的多样化青霉素失活酶，这些酶通常对商业 β-内酰胺酶抑制剂具有抗性。由于在多重耐药（MDR）鲍曼不动杆菌和铜绿假单胞菌中发现了许多此类酶，因此迫切需要新型β-内酰胺酶抑制剂。合成了五种独特的 6-亚烷基-2'-取代的青霉烯酸砜 (1-5)，并针对 OXA-24 进行了测试，OXA-24 是一种临床上重要的 β-内酰胺酶，可灭活碳青霉烯类，并且存在于鲍曼不动杆菌中。基于 Tyr112 和 Met223 在 OXA-24 β-内酰胺酶中的作用，我们还设计了两种变体（Tyr112Ala 和 Tyr112Ala，Met223Ala）来测试由这些残基形成的疏水隧道影响抑制剂识别的假设。针对 OXA-24 和两种 OXA-24 β-内酰胺酶变体的 IC(50) 值范围为 10 ± 1（4 对 WT）至 338 ± 20 nM（5 对 Tyr112Ala、Met223Ala）。化合物