9-deoxo-9-dihydro-9a-(N'-(2-naphthyl)carbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A | 709653-01-0

• 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-(N'-(2-naphthyl)carbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A
• 英文别名: 1-[3-[(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]propyl]-3-naphthalen-2-ylurea
• CAS: 709653-01-0
• 化学式: C₅₁H₈₄N₄O₁₃
• 分子量: 961.247
• InChiKey: GUCFWUGJPPSATF-MQTQZKBLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  68
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  221
• 氢给体数：
  7
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  9-deoxo-9-dihydro-9a-(N'-(2-naphthyl)carbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A 在 甲醇 、 碘 作用下， 反应 26.5h， 以83%的产率得到
  参考文献：
  名称：

  A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides

  摘要：

  Background and PurposeEfficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.Experimental ApproachFour compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.Key ResultsNovel fast‐acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine‐resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin‐containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half‐lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti‐plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow‐acting azithromycin.Conclusion and ImplicationsThe hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.

  DOI：

  10.1111/bph.15292
• 作为产物：
  描述：

  9a-(3-aminopropyl)-9-deoxo-9a-aza-9a-homoerythromycin A 、 2-萘基异氰酸酯 以 二氯甲烷 为溶剂， 反应 1.0h， 以55.2%的产率得到9-deoxo-9-dihydro-9a-(N'-(2-naphthyl)carbamoyl-γ-aminopropyl)-9a-aza-9a-homoerythromycin A
  参考文献：
  名称：

  Novel ureas and thioureas of 15-membered azalides with antibacterial activity against key respiratory pathogens

  摘要：

  The new ureas and thioureas of 15-membered azalides, N ''-substituted 9a-(N'-carbamoyl-gamma-aminopropyl) (4), 9a-(N'-thiocarbamoyl-gamma-aminopropyl) (6), 9a-[N'-(beta-cyanoethyl)-N'-(carbamoyl-gamma-aminopropyl)] (8) and 9a-[N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-gamma-aminopropyl)] (10) of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2), were synthesized and structurally characterized by NMR and IR spectroscopic methods and mass spectrometry. The new compounds were evaluated in vitro against a panel of erythromycin susceptible and erythromycin-resistant Gram-positive and Gram-negative bacterial strains. These compounds displayed an excellent overall antibacterial in vitro activity against erythromycin sensitive Gram-positive strains, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and good against negative strains, Moraxella catarrhalis and Haemophilus influenzae. In addition, several ureas with naphthyl substituents (4f, 4g, 4h) showed better activity in comparison to azithromycin against inducible resistant S. pyogenes. Ureas with naphthyl substituents 4g, 4h and thiourea 8h displayed moderate activity against constitutively resistant S. pneumoniae. (C) 2009 Elsevier Masson SAS. All rights reserved

  DOI：

  10.1016/j.ejmech.2009.02.001

文献信息

• Novel ureas and thioureas of 15-membered azalides with antibacterial activity against key respiratory pathogens
  作者：Mirjana Bukvić Krajačić、Predrag Novak、Miljenko Dumić、Mario Cindrić、Hana Čipčić Paljetak、Nedjeljko Kujundžić

  DOI：10.1016/j.ejmech.2009.02.001

  日期：2009.9

  The new ureas and thioureas of 15-membered azalides, N ''-substituted 9a-(N'-carbamoyl-gamma-aminopropyl) (4), 9a-(N'-thiocarbamoyl-gamma-aminopropyl) (6), 9a-[N'-(beta-cyanoethyl)-N'-(carbamoyl-gamma-aminopropyl)] (8) and 9a-[N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-gamma-aminopropyl)] (10) of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2), were synthesized and structurally characterized by NMR and IR spectroscopic methods and mass spectrometry. The new compounds were evaluated in vitro against a panel of erythromycin susceptible and erythromycin-resistant Gram-positive and Gram-negative bacterial strains. These compounds displayed an excellent overall antibacterial in vitro activity against erythromycin sensitive Gram-positive strains, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and good against negative strains, Moraxella catarrhalis and Haemophilus influenzae. In addition, several ureas with naphthyl substituents (4f, 4g, 4h) showed better activity in comparison to azithromycin against inducible resistant S. pyogenes. Ureas with naphthyl substituents 4g, 4h and thiourea 8h displayed moderate activity against constitutively resistant S. pneumoniae. (C) 2009 Elsevier Masson SAS. All rights reserved
• 9A-Carbamoyl-Y-Aminopropyl- And 9A-Thiocabamoyl-Y-Aminopropyl-Azalides With Antimalarial Activity
  申请人：Ivezic Zrinka

  公开号：US20080113926A1

  公开（公告）日：2008-05-15

  9a-Carbamoyl-γ-aminopropyl- and 9a-thiocarbamoyl-γ-aminopropyl-azalides and their pharmaceutically acceptable derivatives are useful for treatment and prevention of malaria.
• A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides
  作者：Mihaela Peric、Dijana Pešić、Sulejman Alihodžić、Andrea Fajdetić、Esperanza Herreros、Francisco Javier Gamo、Iñigo Angulo‐Barturen、María Belén Jiménez‐Díaz、Santiago Ferrer‐Bazaga、María S. Martínez、Domingo Gargallo‐Viola、Amanda Mathis、Albane Kessler、Mihailo Banjanac、Jasna Padovan、Vlatka Bencetić Mihaljević、Vesna Munic Kos、Mirjana Bukvić、Vesna Eraković Haber、Radan Spaventi

  DOI：10.1111/bph.15292

  日期：2021.1

  Background and PurposeEfficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.Experimental ApproachFour compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.Key ResultsNovel fast‐acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine‐resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin‐containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half‐lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti‐plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow‐acting azithromycin.Conclusion and ImplicationsThe hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy.