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

[en] 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.

Disciplines :

Biochemistry, biophysics & molecular biology
Chemistry

Author, co-author :

Manos-Turvey, Alexandra ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Al-Ashtal, Hiba A.

Needham, Patrick G.

Hartline, Caroll B.

Prichard, Mark N.

Wipf, Peter

Brodsky, Jeffrey L.

Language :

English

Title :

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

Publication date :

2016

Journal title :

Bioorganic and Medicinal Chemistry Letters

ISSN :

0960-894X

eISSN :

1464-3405

Publisher :

Elsevier, United Kingdom

Volume :

Issue :

Pages :

5087-5091

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 04 January 2017

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