N-(((8R,9R,15S)-8,15-dimethyl-6-((2S)-1-(methylamino)propan-2-yl)-5-oxo-5,6,7,8,9,11,12,13,14,15-decahydropyrido[2,3-b][1,9,5]dioxaazacyclotetradecin-9-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide | 1403479-46-8

• 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,15S)-8,15-dimethyl-6-((2S)-1-(methylamino)propan-2-yl)-5-oxo-5,6,7,8,9,11,12,13,14,15-decahydropyrido[2,3-b][1,9,5]dioxaazacyclotetradecin-9-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide
• 英文别名: N-(((8R,9R,15S)-8,15-dimethyl-6-((S)-1-(methylamino)propan-2-yl)-5-oxo-5,6,7,8,9,11,12,13,14,15-decahydropyrido[2,3-b][1,9,5]dioxaazacyclotetradecin-9-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide；N-[[(3S,9R,10R)-3,10-dimethyl-12-[(2S)-1-(methylamino)propan-2-yl]-13-oxo-2,8-dioxa-12,18-diazabicyclo[12.4.0]octadeca-1(14),15,17-trien-9-yl]methyl]-4-fluoro-N-methylbenzenesulfonamide
• CAS: 1403479-46-8
• 化学式: C₂₈H₄₁FN₄O₅S
• 分子量: 564.722
• InChiKey: PWWKADNLAHLTHB-QILISPFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-(((8R,9R,15S)-8,15-dimethyl-6-((2S)-1-(methylamino)propan-2-yl)-5-oxo-5,6,7,8,9,11,12,13,14,15-decahydropyrido[2,3-b][1,9,5]dioxaazacyclotetradecin-9-yl)methyl)-4-fluoro-N-methylbenzenesulfonamide 、 2,5-二氟苯甲醛 在 magnesium sulfate 、 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 反应 19.0h， 以78%的产率得到N-(((8R,9R,15S)-6-((2S)-1-((2,5-difluorobenzyl)(methyl)amino)propan-2-yl)-8,15-dimethyl-5-oxo-5,6,7,8,9,11,12,13,14,15-decahydropyrido[2,3-b][1,9,5]dioxaazacyclotetradecin-9-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
• 作为产物：
  描述：

  (S)-2-(pent-4-en-2-yloxy)nicotinic acid 在 2,6-二甲基吡啶 、 Hoveyda-Grubbs catalyst second generation 、 偶氮二甲酸二异丙酯 、 palladium 10% on activated carbon 、 四丁基氟化铵 、 氢气 、 双(2-氧代-3-恶唑烷基)次磷酰氯 、 sodium hydride 、 potassium carbonate 、 氟化氢吡啶 、 苯硫酚 、 N,N-二异丙基乙胺 、 三苯基膦 、 三氟乙酸 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 mineral oil 为溶剂， 反应 72.92h， 生成 N-(((8R,9R,15S)-8,15-dimethyl-6-((2S)-1-(methylamino)propan-2-yl)-5-oxo-5,6,7,8,9,11,12,13,14,15-decahydropyrido[2,3-b][1,9,5]dioxaazacyclotetradecin-9-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.