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Eur J Med Chem. 2019 Mar 15;166:390-399. doi: 10.1016/j.ejmech.2019.01.081. Epub 2019 Feb 2.

Pharmacophore-based design of novel 3-hydroxypyrimidine-2,4-dione subtypes as inhibitors of HIV reverse transcriptase-associated RNase H: Tolerance of a nonflexible linker.

Author information

1
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.
2
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Christopher S. Bond Life Sciences Center, Columbia, MO, 65211, USA.
3
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO, 65211, USA.
4
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO, 65211, USA; Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
5
Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
6
Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Christopher S. Bond Life Sciences Center, Columbia, MO, 65211, USA; Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA; Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA.
7
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: wangx472@umn.edu.

Abstract

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 μM, and no to marginal RT polymerase (pol) inhibition up to 10 μM. 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.

KEYWORDS:

3-Hydroxypyrimidine-2,4-dione (HPD); Human immunodeficiency virus (HIV); Inhibitors; RNase H; Reverse transcriptase (RT)

PMID:
30739822
PMCID:
PMC6459026
[Available on 2020-03-15]
DOI:
10.1016/j.ejmech.2019.01.081
[Indexed for MEDLINE]

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