Dihydropyrimidinones and -thiones with improved activity against human polyomavirus family members.
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.
Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Alexandra
A
Manos-Turvey
Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA.
Hiba A
HA
Al-Ashtal
Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA.
Patrick G
PG
Needham
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Caroll B
CB
Hartline
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Mark N
MN
Prichard
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA; Center for Chemical Methodologies and Library Development, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Peter
P
Wipf
Department of Biological Science, University of Pittsburgh, A320 Langley Hall, Pittsburgh, PA 15260, USA. Electronic address: jbrodsky@pitt.edu.
Jeffrey L
JL
Brodsky
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D011120:Polyomavirus / Q000187:drug effects*; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D011744:Pyrimidinones
BKPyV; Biginelli; Hsp40; Hsp70; JCPyV; Molecular chaperone; SV40; T antigen; Thiourea