2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 1,2,4-Oxadiazole Derivatives Containing an Aryl Carboxylic Acid Moiety as Potent Sarbecovirus Papain-like Protease Inhibitors

Design, Synthesis, and Biological Evaluation of 1,2,4-Oxadiazole Derivatives Containing an Aryl Carboxylic Acid Moiety as Potent Sarbecovirus Papain-like Protease Inhibitors

  • J Med Chem. 2024 Jun 27;67(12):10211-10232. doi: 10.1021/acs.jmedchem.4c00534.
Bo Qin 1,  Chengwei Wu 2,  Binbin Zhao 3,  Gang Li 2 4,  Baolian Wang 2,  Mengdie Ou 1,  Ziheng Li 1,  Xuli Lang 2,  Peng Li 2,  Jiangning Liu 3,  Sheng Cui 1 4,  Haihong Huang 2 4
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Systems Biology of Pathogens, National Institute of Pathogen Biology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P. R. China.
  • 2 Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China.
  • 3 National Center of Technology Innovation for Animal Models, NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, P. R. China.
  • 4 State Key Laboratory of Respiratory Health and Multimorbidity, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, P. R. China.
PMID: 38871484 DOI: 10.1021/acs.jmedchem.4c00534
Abstract

Papain-like Protease (PLpro) is a promising therapeutic target for its pivotal role in the life cycle of SARS-CoV-2. A series of 1,2,4-oxadiazole derivatives was designed and synthesized via a ring formation strategy based on SARS-CoV-2 PLpro-GRL0617 complex structure. Systematic structure-activity relationship studies revealed that introducing oxadiazole and aryl carboxylic acid moieties to GRL0617 enhanced the enzymatic inhibition activity, affinity, and deubiquitination capacity toward PLpro. 1,2,4-Oxadiazole compounds 13f and 26r, which had PLpro inhibition activity (IC50 = 1.8 and 1.0 μM) and Antiviral activity against SARS-CoV-2 (EC50 = 5.4 and 4.3 μM), exhibited good metabolic stability (t1/2 > 93.2 min) and higher plasma exposure (AUC0-t = 17,380.08 and 24,289.76 ng·h/mL) in mice. Especially, compound 26r with moderate oral bioavailability of 39.1% and potent Antiviral activity is worthy of further studies in vivo. Our findings provide a new insight for the discovery of Antiviral agents targeting PLpro.

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