期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 26, 期 20, 页码 5087-5091出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.08.080
关键词
BKPyV; JCPyV; SV40; Molecular chaperone; Biginelli; T antigen; Hsp70; Hsp40; Thiourea
资金
- National Institutes of Health (The Pittsburgh Center for Kidney Research) [DK079307]
- Howard Hughes Collaborative Innovation Award
- American Australian Association Merck Company Foundation Fellowship
- National Institutes of Health [GM067082]
- National Institutes of Allergy and Infectious Diseases, National Institutes of Health [HHSN2722011000161]
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. (C) 2016 The Authors. Published by Elsevier Ltd.
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