2. Academic Validation
  3. Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members

Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members

  • Bioorg Med Chem Lett. 2016 Oct 15;26(20):5087-5091. doi: 10.1016/j.bmcl.2016.08.080.
Alexandra Manos-Turvey 1,  Hiba A Al-Ashtal 2,  Patrick G Needham 2,  Caroll B Hartline 3,  Mark N Prichard 3,  Peter Wipf 4,  Jeffrey L Brodsky 5
Affiliations

Affiliations

  • 1 Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 2 Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA.
  • 3 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  • 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA; Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 5 Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA. Electronic address: jbrodsky@pitt.edu.
PMID: 27624078 DOI: 10.1016/j.bmcl.2016.08.080
Abstract

Human polyomaviruses are generally latent but can be reactivated in patients whose immune systems are suppressed. Unfortunately, current therapeutics for diseases associated with polyomaviruses are non-specific, have undefined mechanisms of action, or exacerbate the disease. We previously reported on a class of dihydropyrimidinones that specifically target a polyomavirus-encoded protein, T antigen, and/or inhibit a cellular chaperone, HSP70, that is required for virus replication. To improve the Antiviral activity of the existing class of compounds, we performed Biginelli and modified multi-component reactions to obtain new 3,4-dihydropyrimidin-2(1H)-ones and -thiones for biological evaluation. We also compared how substituents at the N-1 versus N-3 position in the pyrimidine affect activity. We discovered that AMT580-043, a N-3 alkylated dihydropyrimidin-2(1H)-thione, inhibits the replication of a disease-causing polyomavirus in Cell Culture more potently than an existing drug, cidofovir.

Keywords

BKPyV; Biginelli; Hsp40; Hsp70; JCPyV; Molecular chaperone; SV40; T antigen; Thiourea.

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