Discovery and optimization of phenazopyridine hydrochloride as novel SARS-CoV-2 RdRp inhibitors

  • Eur J Med Chem. 2025 Apr 15:288:117422. doi: 10.1016/j.ejmech.2025.117422.
Jianyuan Zhao  1 ,  Guoning Zhang  1 ,  YaSheng Li  2 ,  Ling Ma  1 ,  Dongrong Yi  1 ,  Quanjie Li  1 ,  Yu Shi  1 ,  Saisai Guo  1 ,  Tianfu Liu  1 ,  Yujia Wang  1 ,  Xiaoyu Li  1 ,  Yucheng Wang  3 ,  Wenjie Tan  4 ,  Jiabin Li  5 ,  Shan Cen  6
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China.
  • 2. Anhui Province Key Laboratory of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 3. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. Electronic address: [email protected].
  • 4. MHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, China CDC, Beijing, China. Electronic address: [email protected].
  • 5. Anhui Province Key Laboratory of Infectious Diseases & Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: [email protected].
  • 6. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing, China. Electronic address: [email protected].
PMID: 39999742 DOI: 10.1016/j.ejmech.2025.117422
Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen of coronavirus disease (COVID-19) causing a pandemic with growing global transmission. The viral RNA-dependent RNA polymerase (RdRp) is conserved especially for variants of concern (VOCs), making it as an effective antivirals target. Due to the proofreading activity of coronavirus nsp14/nsp10, limited the efficacy of nucleoside analogs in vivo. Herein, we identified that Phenazopyridine hydrochloride (PAP) inhibits SARS-CoV-2 with EC50 of 5.37 μmol/L. Furthermore, PAP can effectively inhibit SARS-CoV-2 RdRp with EC50 value of 7.37 μmol/L, after further optimization, compound PAP-22 exhibits the most potential inhibition, with EC50 of 1.11 μmol/L. PAP and its derivatives can bind directly to SARS-CoV-2 RdRp, fully resistance to the exoribonuclease (ExoN) and exhibit broad spectrum anti-CoV activities. Combined with the current data available on the safe and pharmacokinetics of PAP as an approved drug in clinical use, these results provide a path for the urgently needed antivirals to combat SARS-CoV-2.

Keywords
COVID-19; Phenazopyridine hydrochloride; RdRp inhibitor; SARS-CoV-2; Structure-activity relationships; Synthesis.
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