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

• Published in: European journal of medicinal chemistry Vol. 166; pp. 390 - 399
• Main Authors: Tang, Jing, Do, Ha T., Huber, Andrew D., Casey, Mary C., Kirby, Karen A., Wilson, Daniel J., Kankanala, Jayakanth, Parniak, Michael A., Sarafianos, Stefan G., Wang, Zhengqiang
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.03.2019; Elsevier
• Subjects: 3-Hydroxypyrimidine-2,4-dione (HPD); Catalytic Domain; Chemistry, Medicinal; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Human immunodeficiency virus (HIV); Inhibitors; Inhibitory Concentration 50; Life Sciences & Biomedicine; Molecular Docking Simulation; Pharmacology & Pharmacy; Pyrimidinones - chemistry; Pyrimidinones - metabolism; Pyrimidinones - pharmacology; Reverse transcriptase (RT); Ribonuclease H, Human Immunodeficiency Virus - antagonists & inhibitors; Ribonuclease H, Human Immunodeficiency Virus - chemistry; Ribonuclease H, Human Immunodeficiency Virus - metabolism; RNase H; Science & Technology; Reverse transcriptase (RT); 3-Hydroxypyrimidine-2,4-dione (HPD); RNase H; Inhibitors; Human immunodeficiency virus (HIV); SITE; MECHANISM; INTEGRASE; POLYMERASE; DISCOVERY; BIOLOGICAL EVALUATIONS; POTENT; DIKETO ACID PHARMACOPHORE; OXIDATIVE DECYANATION; RIBONUCLEASE-H
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.01.081

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. [Display omitted] •Novel and highly potent inhibitors of HIV RT-associated RNase H.•Inhibitors uniquely feature a nonflexible carbonyl linkage.•Low nM RNase H inhibition, moderate INST inhibition and marginal RT pol inhibition.•A few analogues exhibited significant antiviral activity with no cytotoxicity.•Molecular modeling study corroborated the RNase H active site binding mode.