Open AccessDiscovery and Structural Optimization of 4-(Aminomethyl)benzamides as Potent Entry Inhibitors of Ebola and Marburg Virus Infections
Author(s) -
Iri. Gaisina,
Norton P. Peet,
Letitia Wong,
Adam Schafer,
Han Cheng,
Manu Anantpadma,
Robert A. Davey,
Gregory R. J. Thatcher,
Lijun Rong
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00463
Subject(s) - ebola virus , marburg virus , ebolavirus , chemistry , virology , virus , filoviridae , mononegavirales , biology , viral disease , paramyxoviridae
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.