Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine derivatives as cathepsin L inhibitor for the treatment of acute lung injury

  • Eur J Med Chem. 2026 Feb 5:303:118463. doi: 10.1016/j.ejmech.2025.118463.
Zhengtong Mao  1 ,  Chunwei Shen  1 ,  Siyu Liang  1 ,  Tao Zhou  2 ,  Jialin Li  3 ,  Peiyu Yang  4 ,  Qiwen Shi  2 ,  Yirong Guo  4 ,  Xingxian Zhang  5
Affiliations
  • 1. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China.
  • 2. Collaborative Innovation Center of Yangtza River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, PR China.
  • 3. Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province, Affiliated First Hospital of Ningbo University, Ningbo, 315010, PR China.
  • 4. Institute of Pesticide and Environmental Toxicology, Zhejiang University, Hangzhou, 310058, PR China.
  • 5. College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, PR China. Electronic address: [email protected].
PMID: 41389412 DOI: 10.1016/j.ejmech.2025.118463
Abstract

Acute lung injury (ALI), a frequent complication among sepsis patients in intensive care units (ICU), is a serious public health problem due to its high mortality rate and the lack of effective treatments in clinic. Cathepsin L (CTSL), which contributes to inflammation, has been demonstrated as a promising therapeutic target for the treatment of ALI. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized. The leading compound 6a showed a high anti-inflammatory activity, achieving inhibition rates of 65 % for IL-6 and 70 % for IL-8 in LPS-stimulated human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Besides, compound 6a successfully suppressed CSTL activity by directly binding to CSTL, and exhibited a good kinase selectivity on CTSL over CTSB, CTSC, CTSS, CTSH and Other inflammation-related kinases. The NF-κB and p38 signaling pathways, which lie downstream of CTSL, were also blocked by compound 6a in LPS-treated cells. Moreover, compound 6a significantly alleviates LPS-induced ALI in mice through its anti-inflammatory effects. In conclusion, compound 6a serves as a selective CTSL inhibitor with prominent anti-inflammatory activities and a potential therapeutic agent for the treatment of ALI.

Keywords
Acute lung injury; Anti-inflammatory; CTSL inhibitor; Pyrrolo[2,3-d]pyrimidine.
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