2. Academic Validation
  3. Discovery of 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivatives as novel anti-inflammatory agents for the treatment of acute lung injury and sepsis

Discovery of 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivatives as novel anti-inflammatory agents for the treatment of acute lung injury and sepsis

  • Eur J Med Chem. 2023 Mar 5;249:115144. doi: 10.1016/j.ejmech.2023.115144.
Jun Yang 1,  Minxiu Wang 1,  Yulan Xu 1,  Jing Liao 1,  Xiang Li 1,  Ying Zhou 1,  Jintian Dai 2,  Xiaobo Li 1,  Pan Chen 3,  Gaozhi Chen 1,  Won-Jea Cho 4,  Nipon Chattipakorn 5,  Aleksandr V Samorodov 6,  Valentin N Pavlov 6,  Yi Wang 7,  Guang Liang 8,  Qidong Tang 9
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.
  • 2 Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325024, Zhejiang, China.
  • 3 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
  • 4 College of Pharmacy, Chonnam National University, Gwangju, 61186, South Korea.
  • 5 Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 6 Department of Pharmacology, Bashkir State Medical University, Ufa City 450005, Russia.
  • 7 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address: [email protected].
  • 8 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325024, Zhejiang, China; School of Pharmacy, Hangzhou Medical College, Hangzhou 311399, Zhejiang, China. Electronic address: [email protected].
  • 9 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325024, Zhejiang, China. Electronic address: [email protected].
PMID: 36708679 DOI: 10.1016/j.ejmech.2023.115144
Abstract

Acute lung injury (ALI) and sepsis, characterized by systemic inflammatory response syndrome, remain the major causes of death in severe patients. Inhibiting the release of proinflammatory cytokines is considered to be a promising method for the treatment of inflammation-related diseases. In this study, a total of 28 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivatives were designed and synthesized and their anti-inflammatory activities in J774A.1 were evaluated. Among them, derivative 13a was found to significantly inhibit lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) on J774A.1, THP-1 and LX-2 cells, and inhibited the activation of the NF-κB pathway. Furthermore, administration of 13ain vivo significantly improved the symptoms in LPS-induced ALI mice, including alleviation of pathological changes in the lung tissue, reduction of pulmonary edema, and inhibition of macrophage infiltration. Moreover, the administration of 13ain vivo significantly promoted survival in LPS-induced sepsis mice. 13a demonstrated favorable pharmacokinetic properties with T1/2 value of 11.8 h and F value of 36.3%. Therefore, this study has identified a novel 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivative, 13a, which is an effective anti-inflammatory agent. The findings have laid a foundation for the further development of agents to treat ALI and sepsis.

Keywords

4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide derivatives; Acute lung injury; Anti-inflammatory; SARs; Sepsis.

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