Journal article
Synthesis, Optimization, and Structure-Activity Relationships of Imidazo[1,2-a]pyrimidines as Inhibitors of Group 2 Influenza A Viruses
Journal of medicinal chemistry, Vol.65(20), pp.14104-14120
10/19/2022
DOI: 10.1021/acs.jmedchem.2c01329
PMID: 36260129
Abstract
The influenza A virus (IAV) is a highly contagious virus that causes pandemics and seasonal epidemics, which are major public health issues. Current anti-influenza therapeutics are limited partly due to the continuous emergence of drug-resistant IAV strains; thus, there is an unmet need to develop novel anti-influenza therapies. Here, we present a novel imidazo[1,2-a]pyrimidine scaffold that targets group 2 IAV entry. We have explored three different regions of the lead compound, and we have developed a series of small molecules that have nanomolar activity against oseltamivir-sensitive and -resistant forms of group 2 IAVs. These small molecules target hemagglutinin (HA), which mediates the viral entry process. Mapping a known small-molecule-binding cavity of the HA structure with resistant mutants suggests that these molecules bind to that cavity and block HA-mediated membrane fusion.
Details
- Title: Subtitle
- Synthesis, Optimization, and Structure-Activity Relationships of Imidazo[1,2-a]pyrimidines as Inhibitors of Group 2 Influenza A Viruses
- Creators
- Saad Alqarni - University of Illinois at ChicagoLaura Cooper - University of Illinois at ChicagoJazmin Galvan AchiRyan Bott - University of Illinois at ChicagoVeeresh Kumar Sali - University of IowaAndrew Brown - University of Illinois at ChicagoBernard D Santarsiero - University of Illinois at ChicagoAleksej Krunic - University of Illinois at ChicagoBalaji Manicassamy - University of IowaNorton P Peet - Chicago BioSolutions Inc., Chicago, Illinois 60612, United StatesPin Zhang - University of Illinois at ChicagoGregory R J Thatcher - University of ArizonaIrina N Gaisina - University of Illinois at ChicagoLijun Rong - University of Illinois at ChicagoTerry W Moore - University of Illinois at Chicago
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.65(20), pp.14104-14120
- DOI
- 10.1021/acs.jmedchem.2c01329
- PMID
- 36260129
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Grant note
- DOI: 10.13039/100000060, name: National Institute of Allergy and Infectious Diseases, award: 1R42 AI155039-01A1, 5R41 AI145727-02
- Language
- English
- Date published
- 10/19/2022
- Academic Unit
- Microbiology and Immunology; Internal Medicine
- Record Identifier
- 9984306757402771
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