9-deoxo-9-dihydro-9a-[β-(N-(βb-cyanoethyl)amino)ethyl]-9a-aza-9a-homoerythromycin A | 905845-87-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 9-deoxo-9-dihydro-9a-[β-(N-(βb-cyanoethyl)amino)ethyl]-9a-aza-9a-homoerythromycin A
• 英文别名: 3-[2-[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-6-yl]ethylamino]propanenitrile
• CAS: 905845-87-6
• 化学式: C₄₂H₇₈N₄O₁₂
• 分子量: 831.101
• InChiKey: VXGXFBXLXRZZCK-PVYXSAIHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  58
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  216
• 氢给体数：
  6
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  异硫氰酸异丙酯 、 9-deoxo-9-dihydro-9a-[β-(N-(βb-cyanoethyl)amino)ethyl]-9a-aza-9a-homoerythromycin A 以 二氯甲烷 为溶剂， 反应 1.0h， 生成
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides

  摘要：

  Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N ''-substituted 9a(N'-carbamoyl-beta-aminoethyl), 9a-(N'-thiocarbamoyl-beta-aminoethyl), 9a-[N'-(beta-cyanoethyl)-N'-(carbarrioyl-beta-aminoethyl)], [N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-beta-aminoethyl)], 9a-{N'-[beta-(ethoxycarbonyl)ethyl]-N'-(carbamoyl-beta-aminoethyl)}, and 9a-[N'-(beta-amidoethyl)-N'-(carbamoyl-beta-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugar; on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.

  DOI：

  10.1021/jm2001585
• 作为产物：
  描述：

  阿奇霉素 在 双氧水 、 三乙基硼氢化锂 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 22.67h， 生成 9-deoxo-9-dihydro-9a-[β-(N-(βb-cyanoethyl)amino)ethyl]-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides

  摘要：

  Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N ''-substituted 9a(N'-carbamoyl-beta-aminoethyl), 9a-(N'-thiocarbamoyl-beta-aminoethyl), 9a-[N'-(beta-cyanoethyl)-N'-(carbarrioyl-beta-aminoethyl)], [N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-beta-aminoethyl)], 9a-{N'-[beta-(ethoxycarbonyl)ethyl]-N'-(carbamoyl-beta-aminoethyl)}, and 9a-[N'-(beta-amidoethyl)-N'-(carbamoyl-beta-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugar; on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.

  DOI：

  10.1021/jm2001585

文献信息

• Novel Antimalarial 9A-Carbamoyl-Aminoalkyl and 9A-Thiocarbamoyl-Aminoalkyl Azalides
  申请人：Bukvic Krajacic Mirjana

  公开号：US20080200404A1

  公开（公告）日：2008-08-21

  Novel 9a-N′-substituted-carbamoyl- and thiocarbamoyl-aminoalkyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A and 3-O-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A compounds having antimalarial activity are claimed. More particularly, the invention relates to 9a-N′-substituted-carbamoyl- and thiocarbamoyl-β-aminoethyl- or -γ-aminopropyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A and 3-O-decladinosyl-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A compounds and to pharmaceutically acceptable derivatives thereof having antimalarial activity.

  本发明涉及具有抗疟活性的9a-N'-取代-氨基甲酰基和硫代氨基甲酰基-氨基烷基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A和3-O-去氯基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A化合物。更具体地，该发明涉及具有抗疟活性的9a-N'-取代-氨基甲酰基和硫代氨基甲酰基-β-氨基乙基或-γ-氨基丙基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A和3-O-去氯基-9a-氮杂-9-去氧-9-二氢-9a-同源红霉素A化合物及其具有抗疟活性的药用可接受衍生物。
• Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides
  作者：Mirjana Bukvić Krajačić、Mihaela Perić、Kirsten S. Smith、Zrinka Ivezić Schönfeld、Dinko Žiher、Andrea Fajdetić、Nedjeljko Kujundžić、Wolfgang Schönfeld、Goran Landek、Jasna Padovan、Dubravko Jelić、Arba Ager、Wilbur K. Milhous、William Ellis、Radan Spaventi、Colin Ohrt

  DOI：10.1021/jm2001585

  日期：2011.5.26

  Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N ''-substituted 9a(N'-carbamoyl-beta-aminoethyl), 9a-(N'-thiocarbamoyl-beta-aminoethyl), 9a-[N'-(beta-cyanoethyl)-N'-(carbarrioyl-beta-aminoethyl)], [N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-beta-aminoethyl)], 9a-N'-[beta-(ethoxycarbonyl)ethyl]-N'-(carbamoyl-beta-aminoethyl)}, and 9a-[N'-(beta-amidoethyl)-N'-(carbamoyl-beta-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugar; on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.