Journal article
Refinement of imidazo[2,1-a]pyrimidines in pursuit of potential drug candidates against group 2 influenza A viruses
European journal of medicinal chemistry, Vol.292, 117679
08/05/2025
DOI: 10.1016/j.ejmech.2025.117679
PMID: 40318481
Abstract
We discovered a series of imidazo[1,2-a]pyrimidines as potent, group 2 selective inhibitors of influenza A viruses (IAVs) that target the hemagglutinin-mediated viral entry process. Preliminary hit-to-lead optimization efforts afforded promising IAV inhibitors with improved activity against infectious H7N7 and H3N2 viruses. We now report a more comprehensive cycle of structure-activity relationship studies and optimization of metabolic stability, and overall druglike properties of this series of imidazo[1,2-a]pyrimidines, which allowed in the identification of two lead compounds that show promise as preclinical candidates. Compounds 10 and 12 inhibited pseudotyped H7N1 with EC50 values of 0.09 and 0.47 μM, respectively. They were among the most potent compounds in the viral replication assay when tested against infectious H3N2 IAV, and they also demonstrated remarkable activity against avian influenza viruses; these data designated these imidazo[1,2-a]pyrimidines as potent broad-spectrum group 2 IAV inhibitors. Compounds 10 and 12 exhibit dissimilar but desirable drug metabolism and pharmacokinetics (DMPK) profiles, and therefore they offer different options for specific and effective patient treatment.
[Display omitted]
•New imidazopyrimidines target hemagglutinin-mediated influenza A viral entry.•Show remarkable antiviral activity against highly pathogenic H3N2 AIV strain.•Lead compounds demonstrate significant activity against avian influenza viruses.•Structural optimization rescued the compounds from Dimroth rearrangement.•Lead compounds exhibit desirable metabolic stability and pharmacokinetic profiles.
Details
- Title: Subtitle
- Refinement of imidazo[2,1-a]pyrimidines in pursuit of potential drug candidates against group 2 influenza A viruses
- Creators
- Malaika D. Argade - University of Illinois Urbana-ChampaignVarada Anirudhan - University of Illinois Urbana-ChampaignSean P. Bradley - University of Illinois Urbana-ChampaignŁukasz Tomorowicz - University of Illinois Urbana-ChampaignRyan Bott - University of Illinois Urbana-ChampaignBoopathi Sownthirarajan - University of IowaChristian A. Zielinski - University of Illinois Urbana-ChampaignJohn P. Sloan - University of Illinois Urbana-ChampaignDejan S. Nikolic - University of Illinois Urbana-ChampaignArsen M. Gaisin - University of Illinois Urbana-ChampaignTerry W. Moore - University of Illinois Urbana-ChampaignBalaji Manicassamy - University of IowaNorton P. Peet - Chicago BioSolutions Inc., Chicago, IL, 60612, United StatesLijun Rong - University of Illinois Urbana-ChampaignIrina N. Gaisina - University of Illinois Urbana-Champaign
- Resource Type
- Journal article
- Publication Details
- European journal of medicinal chemistry, Vol.292, 117679
- DOI
- 10.1016/j.ejmech.2025.117679
- PMID
- 40318481
- NLM abbreviation
- Eur J Med Chem
- ISSN
- 0223-5234
- eISSN
- 1768-3254
- Publisher
- Elsevier Masson SAS
- Grant note
- National Institutes of Health: R42AI155039-02
This work was partially supported by the National Institutes of Health (R42AI155039-02) .
- Language
- English
- Date published
- 08/05/2025
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984820561902771
Metrics
4 Record Views