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

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 e...

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Published inJournal of medicinal chemistry Vol. 63; no. 13; pp. 7211 - 7225
Main Authors Gaisina, Irina N, Peet, Norton P, Wong, Letitia, Schafer, Adam M, Cheng, Han, Anantpadma, Manu, Davey, Robert A, Thatcher, Gregory R. J, Rong, Lijun
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 09.07.2020
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
NIEMANN-PICK C1
DISEASES
FILOVIRUS
ANTIBODY
T-705 FAVIPIRAVIR
GLYCOPROTEIN
L-GENE
NEUTRALIZATION
SMALL-MOLECULE INHIBITOR
INSIGHTS
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Summary: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.
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The manuscript was prepared through contributions of all authors. All authors have given approval to the final version of the manuscript.
Author Contributions
Present Addresses: M.A. and R.A.D.: Department of Microbiology, Boston University, 620 Albany Street, Boston, Massachusetts 02118, United States.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00463