<i>N</i>-Hydroxypiridinedione: A Privileged Heterocycle for Targeting the HBV RNase H
Dimitrios Moianos,
Maria Makri,
Georgia-Myrto Prifti,
Aristeidis Chiotellis,
Alexandros Pappas,
Molly E. Woodson,
Razia Tajwar,
John E. Tavis,
Grigoris Zoidis
Affiliations
Dimitrios Moianos
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
Maria Makri
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
Georgia-Myrto Prifti
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
Aristeidis Chiotellis
Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Center for Scientific Research “Demokritos”, 15310 Athens, Greece
Alexandros Pappas
Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Center for Scientific Research “Demokritos”, 15310 Athens, Greece
Molly E. Woodson
Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
Razia Tajwar
Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
John E. Tavis
Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
Grigoris Zoidis
Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of N-hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg2+ ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC50 values in the low μM range (1.1–7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure–activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents.
