Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase

• Published in: European journal of medicinal chemistry Vol. 133; pp. 85 - 96
• Main Authors: Tang, Jing, Vernekar, Sanjeev Kumar V., Chen, Yue-Lei, Miller, Lena, Huber, Andrew D., Myshakina, Nataliya, Sarafianos, Stefan G., Parniak, Michael A., Wang, Zhengqiang
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 16.06.2017; Elsevier
• Subjects: 2-hydroxyisoquinoline-1,3-diones; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Catalytic Domain - drug effects; Chemistry, Medicinal; Drug Design; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Inhibitor; Isoquinolines - chemistry; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Molecular Docking Simulation; Pharmacology & Pharmacy; Reverse transcriptase; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Ribonuclease H - antagonists & inhibitors; Ribonuclease H - metabolism; RNase H; Science & Technology; RNase H; Inhibitor; Reverse transcriptase; HIV; 2-hydroxyisoquinoline-1,3-diones; RNASE-H; DESIGN; COMPLEX; VIRUS; ASSAY; INTEGRASE; NNRTIS; DRUG-RESISTANCE; NUCLEOSIDE; NONNUCLEOSIDE INHIBITOR
• DOI: 10.1016/j.ejmech.2017.03.059
• ISSN: 0223-5234

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8–9 as exemplified with compounds 8c and 9c. [Display omitted] •HID subtypes were synthesized and tested against HIV RT-associated RNase H and pol.•Subtypes 4, 5 and 9 inhibited both RNase H and pol whereas 6–8 selectively inhibited RNase H.•Compounds 8c and 9c were identified as potent and selective inhibitors of HIV RNase H.•Extensive molecular modeling largely corroborated observed inhibitory activities.