Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 166, Issue -, Pages 390-399Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.01.081
Keywords
Human immunodeficiency virus (HIV); Reverse transcriptase (RT); RNase H; Inhibitors; 3-Hydroxypyrimidine-2,4-dione (HPD)
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Funding
- National Institutes of Health [AI100890]
- Center for Drug Design, University of Minnesota
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The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low mu M, and no to marginal RT polymerase (pol) inhibition up to 10 mu M. A few analogues also demonstrated significant antiviral activity without cytotoxicity. The overall inhibitory profile is comparable to or better than that of previous HPD subtypes with a flexible C-6 linker, suggesting that the nonflexible carbonyl linker can be tolerated in the design of novel HIV RNase H active site inhibitors. (C) 2019 Elsevier Masson SAS. All rights reserved.
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