Aryl and Arylalkyl Substituted 3‐Hydroxypyridin‐2(1H)‐ones: Synthesis and Evaluation as Inhibitors of Influenza A Endonuclease

Abstract

Seasonal influenza infections are associated with an estimated 250–500 000 deaths annually. Resistance to the antiviral M2 ion‐channel inhibitors has largely invalidated their clinical utility. Resistance to neuraminidase inhibitors has also been observed in several influenza A virus (IAV) strains. These data have prompted research on inhibitors that target the cap‐snatching endonuclease activity of the polymerase acidic protein (PA). Baloxavir marboxil (Xofluza®), recently approved for clinical use, inhibits cap‐snatching endonuclease. Resistance to Xofluza® has been reported in both in vitro systems and in the clinic. An X‐ray crystallographic screening campaign of a fragment library targeting IAV endonuclease identified 5‐chloro‐3‐hydroxypyridin‐2(1H)‐one as a bimetal chelating agent at the active site. We have reported the structure–activity relationships for 3‐hydroxypyridin‐2(1H)‐ones and 3‐hydroxyquinolin‐2(1H)‐ones as endonuclease inhibitors. These studies identified two distinct binding modes associated with inhibition of this enzyme that are influenced by the presence of substituents at the 5‐ and 6‐positions of 3‐hydroxypyridin‐2(1H)‐ones. Herein we report the structure–activity relationships associated with various para‐substituted 5‐phenyl derivatives of 6‐(p‐fluorophenyl)‐3‐hydroxypyridin‐2(1H)‐ones and the effect of using naphthyl, benzyl, and naphthylmethyl groups as alternatives to the p‐fluorophenyl substituent on their activity as endonuclease inhibitors.

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

“…Medicinal chemistry targeting HIV RNase H active site is well documented [7][8][9]. Reported inhibitor types, such as 2-hydroxyisoquinolinedione (HID) [10][11], β-thujaplicinol [12], dihydroxycoumarin [13], diketoacid (DKA) [14], HPD [15][16][17] and 3-hydroxy thienopyrimidine-2,4-dione [18], largely build on a chelating core capable of binding two divalent metal ions, a critical pharmacophore component also found in inhibitors of HIV INST [19][20][21][22], influenza PA endonuclease [23][24][25][26][27] and human cytomegalovirus (HCMV) terminase pUL89 [28][29][30], all sharing a similar active site fold and a divalent metal requirement for catalytic activity [31]. Notably, structurally more elaborate inhibitor types, including pyrimidinol carboxylic acid 1 [32], hydroxynaphthyridine 2 [33], pyridopyrimidone 3 [34], hydroxypyridonecarboxylic acid (HPCA) 4 [35], redesigned HID 5 [36], and redesigned HPD 6 [37][38][39] (Figure 1), all contain an additional hydrophobic aromatic moiety (cyan) connected to the chelating core through a one-atom linker (blue), constituting an RNase H inhibitor pharmacophore reminiscent of that observed for canonical INSTIs [40][41].…”

Contemporary medicinal chemistry strategies for the discovery and optimization of influenza inhibitors targeting vRNP constituent proteins

“… 48 carried out a fragment-based screening using the high-resolution crystal structure of 2009 H1N1 influenza A endonuclease domain (PA N ), leading to the identification of 3-hydroxypyridin-2(1 H )-ones as a new bimetallic chelating ligand for tightly binding the active site of PA endonuclease. Subsequently, based on structural optimization, the researchers developed two novel series of compounds (3-hydroxypyridin-2(1 H )-ones and 3-hydroxyquinolin-2(1 H )-ones) as PA endonuclease inhibitors 49 , 50 .…”

Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

“…Several aryl and alkyl substituted 3-hydroxypyridin(1H)-2-ones were studied by LaVoie and co-workers 77 for their ability to inhibit IAV endonuclease activity. Their endonuclease inhibitory activities are provided.…”