Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment

Yongzhi Chen; Kunyu Lu; Binhao Rong; Yuanmei Wen; Guanguan Li; Shuo Li; Deyin Guo; Qifan Zhou; Shuwen Liu; Xumu Zhang

doi:10.1021/acs.jmedchem.4c01979

Discovery of Novel Thiophene-Based Baloxavir Derivatives as Potent Cap-Dependent Endonuclease Inhibitors for Influenza Treatment

J Med Chem. 2024 Dec 26;67(24):22039-22054. doi: 10.1021/acs.jmedchem.4c01979. Epub 2024 Dec 10.

Authors

Yongzhi Chen¹, Kunyu Lu², Binhao Rong², Yuanmei Wen¹, Guanguan Li³, Shuo Li¹, Deyin Guo⁴, Qifan Zhou¹, Shuwen Liu^{2

5}, Xumu Zhang¹

Affiliations

¹ Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China.
² Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
³ Shenzhen AntiV Pharma Co., Ltd., Shenzhen, Guangdong 518081, China.
⁴ Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.
⁵ State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.

PMID: 39658517
DOI: 10.1021/acs.jmedchem.4c01979

Abstract

The genetic recombination and antigenic variation of influenza viruses may decrease the efficacy of antiviral vaccines, highlighting the imperativeness of developing novel anti-influenza agents. Herein, a series of thiophene-based compounds were designed and synthesized as potent anti-influenza agents. Among them, ATV2301 exhibited an excellent anti-influenza activity (EC₅₀, H1N1 = 1.88 nM, H3N2 = 4.77 nM), a higher safety index (SI, H1N1 = 18218, H3N2 = 7180), and a remarkably improved oral bioavailability (F = 71.60%). The prodrug ATV2301A demonstrated strong therapeutic efficacy and protection in H1N1-infected BALB/c mice, with low toxicity and broad tissue distribution. ATV2301 also exhibited high stability in both human and mouse liver microsomes. Mechanistic studies indicated that ATV2301's anti-influenza activity was due to its effects on polymerase acid protein (PA), nuclear protein (NP), and RNA-dependent RNA polymerase (RdRp). Additionally, ATV2301 showed potent activities against clinical isolates of anti-influenza A virus (IAV) and anti-influenza B virus (IBV), positioning it as a promising cap-dependent endonuclease inhibitor for further clinical research.

MeSH terms

Animals
Antiviral Agents* / chemistry
Antiviral Agents* / pharmacokinetics
Antiviral Agents* / pharmacology
Dibenzothiepins*
Dogs
Drug Discovery
Endonucleases* / antagonists & inhibitors
Endonucleases* / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Influenza A Virus, H1N1 Subtype* / drug effects
Influenza A Virus, H3N2 Subtype / drug effects
Influenza B virus / drug effects
Influenza, Human / drug therapy
Influenza, Human / virology
Madin Darby Canine Kidney Cells
Mice
Mice, Inbred BALB C*
Microsomes, Liver / metabolism
Morpholines* / chemistry
Morpholines* / pharmacology
Orthomyxoviridae Infections / drug therapy
Orthomyxoviridae Infections / virology
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology
Structure-Activity Relationship
Thiophenes* / chemical synthesis
Thiophenes* / chemistry
Thiophenes* / pharmacokinetics
Thiophenes* / pharmacology
Triazines* / chemical synthesis
Triazines* / chemistry
Triazines* / pharmacokinetics
Triazines* / pharmacology

Substances

Antiviral Agents
Thiophenes
baloxavir
Dibenzothiepins
Triazines
Endonucleases
Morpholines
Pyridones
Enzyme Inhibitors