1-Hydroxy-1,8-napthyridinone (DHN) Analogs Potently Inhibit Monkeypox Virus Resolvase (Mpr)

  • J Med Chem. 2026 Jan 8;69(1):698-714. doi: 10.1021/acs.jmedchem.5c03356.
Samuel Offei  1 ,  Jacob P Mahoney  1 ,  Ziyue Wang  2 ,  Anil Pant  2 ,  Won Hee Ryu  1 ,  Roshan Katekar  1 ,  Jiashu Xie  1 ,  Zhilong Yang  2 ,  Zhengqiang Wang  1
Affiliations
  • 1. Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 2. Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas 77843, United States.
PMID: 41427895 DOI: 10.1021/acs.jmedchem.5c03356
Abstract

The virally encoded Holliday junction resolvase is required for poxvirus genome replication and viral maturation. Previously, a 1-hydroxy-1,8-napthyridinone (DHN) analog (3) was discovered as an inhibitor hit of mpox resolvase (Mpr). Herein, we have conducted Mpr-based comprehensive structure-activity relationship (SAR) studies of compound 3 via the synthesis of 70 analogs of four distinct subtypes. The SAR identified a phenyl ring and a biphenyl moiety as the optimal substituent for C-3 and C-6/C-5, respectively, and that C-5 analogs are generally better than their C-6 regio-isomers. Against vaccinia virus (VACV), the tested new analogs demonstrated Antiviral activity in the low μM to nM range. In the end, the best compound 5-1 conferred drastically improved inhibitory profiles against Mpr (IC50 = 36 nM, 10-fold improvement) and VACV (EC50 = 3.2 nM, 400-fold improvement) over compound 3, with significantly lower binding free energy as predicted from free energy perturbation, and highly favorable ADME properties.

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