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.
- 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: [email protected].
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.