2. Academic Validation
  3. Discovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections

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

  • J Med Chem. 2020 Jul 9;63(13):7211-7225. doi: 10.1021/acs.jmedchem.0c00463.
Irina N Gaisina 1 2,  Norton P Peet 2,  Letitia Wong 2,  Adam M Schafer 3,  Han Cheng 3,  Manu Anantpadma 4 5,  Robert A Davey 4 5,  Gregory R J Thatcher 1,  Lijun Rong 3
Affiliations

Affiliations

  • 1 UICentre (Drug Discovery @ UIC) and Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
  • 2 Chicago BioSolutions Inc., 2242 W Harrison Street, Chicago, Illinois 60612, United States.
  • 3 College of Medicine, Department of Microbiology and Immunology, University of Illinois at Chicago, 909 S Wolcott Ave, Chicago, Illinois 60612, United States.
  • 4 Texas Biomedical Research Institute, 8715 W Military Drive, San Antonio, Texas 78227, United States.
  • 5 Department of Microbiology, Boston University, 620 Albany Street, Boston, Massachusetts 02118, United States.
PMID: 32490678 DOI: 10.1021/acs.jmedchem.0c00463
Abstract

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 41-50). Compounds 20, 23, 32, 33, and 35 are superior inhibitors of Ebola (Mayinga) and Marburg (Angola) infectious viruses. Representative compounds (20, 32, and 35) have shown good metabolic stability in plasma and liver microsomes (rat and human), and 32 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.

Figures
Products