Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections

Details

• Alternative Title:
  J Med Chem
• Personal Author:
  Gaisina, Irina N. ; Peet, Norton P. ; Wong, Letitia ; Schafer, Adam M. ; Cheng, Han ; Anantpadma, Manu ; Davey, Robert A. ; Thatcher, Gregory R. J. ; Rong, Lijun
• Description:
  The recent Ebola epidemics in West Africa underscore the great need for effective and practical therapies for future Ebola virus outbreaks. We have discovered a new series of remarkably potent small molecule inhibitors of Ebola virus entry. These 4-(aminomethyl)benzamide-based inhibitors are also effective against Marburg virus. Synthetic routes to these compounds allowed for the preparation of a wide variety of structures, including a conformationally restrained subset of indolines (compounds |-|). Compounds |, |, |, |, and | are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (|, |, and |) have shown good metabolic stability in plasma and liver microsomes (rat and human), and | did not inhibit CYP3A4 nor CYP2C9. These 4-(aminomethyl)benzamides are suitable for further optimization as inhibitors of filovirus entry, with the potential to be developed as therapeutic agents for the treatment and control of Ebola virus infections.
• Subjects:
  A549 Cells Animals Antiviral Agents Article Benzamides Chlorocebus Aethiops Cytochrome P-450 CYP3A Inhibitors Drug Evaluation, Preclinical Hemorrhagic Fever, Ebola Humans Marburg Virus Disease Microsomes, Liver Molecular Docking Simulation Structure-Activity Relationship Toremifene Vero Cells Viral Envelope Proteins Virus Internalization

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• Source:
  J Med Chem. 63(13):7211-7225
• Pubmed ID:
  32490678
• Pubmed Central ID:
  PMC7671190
• Document Type:
  Journal Article
• Funding:
  R41 AI126971/AI/NIAID NIH HHSUnited States/ ; R42 AI126971/AI/NIAID NIH HHSUnited States/ ; R43 CK000495/CK/NCEZID CDC HHSUnited States/
• Volume:
  63
• Issue:
  13
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:4b6a01b98f7a24139efd6cad88268d0fc51451edb8afd396d5a84bc0485a9c02
• Download URL:
  https://stacks.cdc.gov/view/cdc/97471/cdc_97471_DS1.pdf
• File Type:
  [PDF - 1.79 MB ]