N-(((8R,9R)-14-(3-(3,5-dimethylisoxazol-4-yl)ureido)-11-((2S)-1-((4-methoxybenzyl)oxy)propan-2-yl)-9-methyl-12-oxo-2,3,4,5,6,8,9,10,11,12-decahydro-1H-benzo[g][1,5,9]oxadiazacyclotetradecin-8-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide | 1403478-61-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: N-(((8R,9R)-14-(3-(3,5-dimethylisoxazol-4-yl)ureido)-11-((2S)-1-((4-methoxybenzyl)oxy)propan-2-yl)-9-methyl-12-oxo-2,3,4,5,6,8,9,10,11,12-decahydro-1H-benzo[g][1,5,9]oxadiazacyclotetradecin-8-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide
• 英文别名: N-(((8R,9R)-14-(3-(3,5-dimethylisoxazol-4-yl)ureido)-11-((S)-1-((4-methoxybenzyl)oxy)propan-2-yl)-9-methyl-12-oxo-2,3,4,5,6,8,9,10,11,12-decahydro-1H-benzo[g][1,5,9]oxadiazacyclotetradecin-8-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide；1-(3,5-dimethyl-1,2-oxazol-4-yl)-3-[(9R,10R)-9-[[(4-fluorophenyl)sulfonyl-methylamino]methyl]-12-[(2S)-1-[(4-methoxyphenyl)methoxy]propan-2-yl]-10-methyl-13-oxo-8-oxa-2,12-diazabicyclo[12.4.0]octadeca-1(14),15,17-trien-16-yl]urea
• CAS: 1403478-61-4
• 化学式: C₄₁H₅₃FN₆O₈S
• 分子量: 808.972
• InChiKey: MGAXGUFWDJMWEX-ZEVRPEKRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  57
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  173
• 氢给体数：
  3
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  N-((2R,3R)-2-((tert-butyldimethylsilyl)oxy)-4-(((2S)-1-((4-methoxybenzyl)oxy)propan-2-yl)amino)-3-methylbutyl)-4-fluoro-N-methylbenzenesulfonamide 在 2,6-二甲基吡啶 、 4-二甲氨基吡啶 、 Hoveyda-Grubbs catalyst second generation 、 tin(II) chloride dihdyrate 、 palladium 10% on activated carbon 、 四丁基氟化铵 、 氢气 、 sodium hydride 、 氟化氢吡啶 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 107.0h， 生成 N-(((8R,9R)-14-(3-(3,5-dimethylisoxazol-4-yl)ureido)-11-((2S)-1-((4-methoxybenzyl)oxy)propan-2-yl)-9-methyl-12-oxo-2,3,4,5,6,8,9,10,11,12-decahydro-1H-benzo[g][1,5,9]oxadiazacyclotetradecin-8-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide
  参考文献：
  名称：

  Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Toward the Development of Novel Antimalarial Agents

  摘要：

  Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.

  DOI：

  10.1021/jm500994n

文献信息

• [EN] MACROLACTAM COMPOUNDS AND METHODS FOR THE TREATMENT OF MALARIA<br/>[FR] COMPOSÉS MACROLACTAMES ET MÉTHODES DE TRAITEMENT DU PALUDISME
  申请人：BROAD INST INC

  公开号：WO2012142457A3

  公开（公告）日：2013-02-07
• Diversity-Oriented Synthesis-Facilitated Medicinal Chemistry: Toward the Development of Novel Antimalarial Agents
  作者：Eamon Comer、Jennifer A. Beaudoin、Nobutaka Kato、Mark E. Fitzgerald、Richard W. Heidebrecht、Maurice duPont Lee、Daniela Masi、Marion Mercier、Carol Mulrooney、Giovanni Muncipinto、Ann Rowley、Keila Crespo-Llado、Adelfa E. Serrano、Amanda K. Lukens、Roger C. Wiegand、Dyann F. Wirth、Michelle A. Palmer、Michael A. Foley、Benito Munoz、Christina A. Scherer、Jeremy R. Duvall、Stuart L. Schreiber

  DOI：10.1021/jm500994n

  日期：2014.10.23

  Here, we describe medicinal chemistry that was accelerated by a diversity-oriented synthesis (DOS) pathway, and in vivo studies of our previously reported macrocyclic antimalarial agent that derived from the synthetic pathway. Structure-activity relationships that focused on both appendage and skeletal features yielded a nanomolar inhibitor of P. falciparum asexual blood-stage growth with improved solubility and microsomal stability and reduced hERG binding. The build/couple/pair (B/C/P) synthetic strategy, used in the preparation of the original screening library, facilitated medicinal chemistry optimization of the antimalarial lead.