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

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-02-20 DOI:10.1016/j.ejmech.2025.117422

Jianyuan Zhao , Guoning Zhang , YaSheng Li , Ling Ma , Dongrong Yi , Quanjie Li , Yu Shi , Saisai Guo , Tianfu Liu , Yujia Wang , Xiaoyu Li , Yucheng Wang , Wenjie Tan , Jiabin Li , Shan Cen

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引用次数: 0

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.

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.