2. Academic Validation
  3. Rational design and optimization of acylthioureas as novel potent influenza virus non-nucleoside polymerase inhibitors

Rational design and optimization of acylthioureas as novel potent influenza virus non-nucleoside polymerase inhibitors

  • Eur J Med Chem. 2023 Nov 5;259:115678. doi: 10.1016/j.ejmech.2023.115678.
Xinjin Liu 1,  Zhichao Xu 2,  Jinsen Liang 2,  Ting Xu 2,  Wenting Zou 2,  Lijun Zhu 2,  Yihe Wu 2,  Chune Dong 2,  Ke Lan 3,  Shuwen Wu 4,  Hai-Bing Zhou 5
Affiliations

Affiliations

  • 1 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 2 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 3 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China. Electronic address: [email protected].
  • 5 Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology, Provincial Key Laboratory of Developmentally Originated Disease, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (MOE) and Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan, 430071, China. Electronic address: [email protected].
PMID: 37531746 DOI: 10.1016/j.ejmech.2023.115678
Abstract

Evidence suggests that rapidly evolving virus subvariants risk rendering current vaccines and anti-influenza drugs ineffective. Hence, exploring novel scaffolds or new targets of anti-influenza drugs is of great urgency. Herein, we report the discovery of a series of acylthiourea derivatives produced via a scaffold-hopping strategy as potent Antiviral agents against influenza A and B subtypes. The most effective compound 10m displayed subnanomolar activity against H1N1 proliferation (EC50 = 0.8 nM) and exhibited inhibitory activity toward other influenza strains, including influenza B virus and H1N1 variant (H1N1, H274Y). Additionally, druggability evaluation revealed that 10m exhibited favorable pharmacokinetic properties and was metabolically stable in liver microsome preparations from three different species as well as in human plasma. In vitro and in vivo toxicity studies confirmed that 10m demonstrated a high safety profile. Furthermore, 10m exhibited satisfactory Antiviral activity in a lethal Influenza Virus mouse model. Moreover, mechanistic studies indicated that these acylthiourea derivatives inhibited Influenza Virus proliferation by targeting Influenza Virus RNA-dependent RNA polymerase. Thus, 10m is a potential lead compound for the further exploration of treatment options for influenza.

Keywords

Acylthiourea; Anti-influenza; Druggability evaluation; Non-nucleoside polymerase inhibitors; RNA-dependent RNA polymerase.

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