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

作者：Manos Turvey Alexandra; Al Ashtal Hiba A; Needham Patrick G; Hartline Caroll B; Prichard Mark N; Wipf Peter; Brodsky Jeffrey L^*

来源：Bioorganic & Medicinal Chemistry Letters, 2016, 26(20): 5087-5091.

DOI：10.1016/j.bmcl.2016.08.080

• BKPyV
• JCPyV
• SV40
• Molecular chaperone
• Biginelli
• T antigen
• Hsp70
• Hsp40
• Thiourea

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.

• 出版日期2016-10-15