(±)-6-amino-3-methyl-4-isopropyl-4-[3-(pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (±)-6-amino-3-methyl-4-isopropyl-4-[3-(pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
• 英文别名: 6-amino-3-methyl-4-propan-2-yl-4-[3-pyrimidin-4-yl-5-(trifluoromethyl)phenyl]-2H-pyrano[2,3-c]pyrazole-5-carbonitrile
• 化学式: C₂₂H₁₉F₃N₆O
• 分子量: 440.428
• InChiKey: GQQJPYKQBYSFLI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  32
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2-methyl-1-[3-(pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]propan-1-one 在 哌啶 、 吡啶 、 四氯化钛 作用下， 以 1,4-二氧六环 、 乙醇 、 氯仿 、 甲苯 为溶剂， 反应 51.5h， 生成 (±)-6-amino-3-methyl-4-isopropyl-4-[3-(pyrimidin-4-yl)-5-(trifluoromethyl)phenyl]-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
  参考文献：
  名称：

  Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures

  摘要：

  Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development., We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t(1/2) > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 angstrom resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.

  DOI：

  10.1021/acs.jmedchem.7b00008

文献信息

• Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures
  作者：Geoffrey Schwertz、Matthias C. Witschel、Matthias Rottmann、Roger Bonnert、Ubolsree Leartsakulpanich、Penchit Chitnumsub、Aritsara Jaruwat、Wanwipa Ittarat、Anja Schäfer、Raphael A. Aponte、Susan A. Charman、Karen L. White、Abhijit Kundu、Surajit Sadhukhan、Mel Lloyd、Gail M. Freiberg、Myron Srikumaran、Marc Siggel、Adrian Zwyssig、Pimchai Chaiyen、François Diederich

  DOI：10.1021/acs.jmedchem.7b00008

  日期：2017.6.22

  Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development., We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t(1/2) > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 angstrom resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.