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

Jing Tang; Ha T Do; Andrew D Huber; Mary C Casey; Karen A Kirby; Daniel J Wilson; Jayakanth Kankanala; Michael A Parniak; Stefan G Sarafianos; Zhengqiang Wang

doi:10.1016/j.ejmech.2019.01.081

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

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

Authors

Affiliations

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).

MeSH terms

Catalytic Domain
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
HIV Reverse Transcriptase / metabolism*
HIV-1 / drug effects
HIV-1 / enzymology*
Inhibitory Concentration 50
Molecular Docking Simulation
Pyrimidinones / chemistry*
Pyrimidinones / metabolism
Pyrimidinones / pharmacology*
Ribonuclease H, Human Immunodeficiency Virus / antagonists & inhibitors*
Ribonuclease H, Human Immunodeficiency Virus / chemistry
Ribonuclease H, Human Immunodeficiency Virus / metabolism

Substances

Enzyme Inhibitors
Pyrimidinones
HIV Reverse Transcriptase
Ribonuclease H, Human Immunodeficiency Virus

Abstract

MeSH terms

Substances

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