6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H

• Published in: European journal of medicinal chemistry Vol. 156; pp. 680 - 691
• Main Authors: Wang, Lei, Tang, Jing, 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 05.08.2018; Elsevier
• Subjects: 3-Hydroxypyrimidine-2,4-dione (HPD); Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Catalytic Domain - drug effects; Cell Line; Chemistry, Medicinal; Drug Design; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - enzymology; Human immunodeficiency virus (HIV); Humans; Inhibitors; Life Sciences & Biomedicine; Methylation; Models, Molecular; Pharmacology & Pharmacy; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Ribonuclease H, Human Immunodeficiency Virus - antagonists & inhibitors; Ribonuclease H, Human Immunodeficiency Virus - chemistry; Ribonuclease H, Human Immunodeficiency Virus - metabolism; RNase H; Science & Technology; Structure-Activity Relationship; Structure-activity-relationship (SAR); 3-Hydroxypyrimidine-2,4-dione (HPD); RNase H; Inhibitors; Structure-activity-relationship (SAR); Human immunodeficiency virus (HIV); DESIGN; DOMAIN; ACTIVE-SITE; INTEGRASE; ANALOGS; HUMAN-IMMUNODEFICIENCY-VIRUS; BIOLOGICAL EVALUATIONS; 3-HYDROXYPYRIMIDINE-2,4-DIONES; DUAL INHIBITORS; RIBONUCLEASE-H
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.07.035

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested. In cell-based assays, a few analogues inhibited HIV in low micromolar range without cytotoxicity at concentrations up to 100 μM. [Display omitted] •Novel and highly potent inhibitors of HIV RT-associated RNase H.•Low nM RNase H inhibition without inhibiting INST or RT pol.•A few analogues exhibited significant antiviral activity with no cytotoxicity.•Molecular modeling study corroborated the RNase H active site binding mode.