2. Academic Validation
  3. Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2

Design, synthesis and biological evaluation of peptidomimetic benzothiazolyl ketones as 3CLpro inhibitors against SARS-CoV-2

  • Eur J Med Chem. 2023 Sep 5;257:115512. doi: 10.1016/j.ejmech.2023.115512.
Hanxi Yang 1,  Mengyuan You 2,  Xiaoyang Shu 3,  Jingyao Zhen 4,  Mengwei Zhu 5,  Tiantian Fu 5,  Yan Zhang 6,  Xiangrui Jiang 4,  Leike Zhang 7,  Yechun Xu 8,  Yumin Zhang 9,  Haixia Su 10,  Qiumeng Zhang 11,  Jingshan Shen 6
Affiliations

Affiliations

  • 1 College of Chemistry, Zhengzhou University, 100 Kexuedadao Road, Zhengzhou, 450001, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
  • 5 College of Pharmacy, An Hui University of Traditional Chinese Medicine, Hefei, 230012, China; Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong, 226133, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China; Hubei Jiangxia Laboratory, Wuhan, 430200, China.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 9 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China. Electronic address: ymzhang@wh.iov.cn.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: suhaixia1@simm.ac.cn.
  • 11 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. Electronic address: qmzhang@simm.ac.cn.
PMID: 37253309 DOI: 10.1016/j.ejmech.2023.115512
Abstract

A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CLpro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC50 = 0.110 μM) and 11e had the best microsomal stability (t1/2 > 120 min) and good Enzyme activity (IC50 = 0.868 μM). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC(0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g-11j based on 11e. Among them, 11j exhibited the best Enzyme inhibition activity against SARS-CoV-2 3CLpro (IC50 = 1.646 μM), the AUC(0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC50 = 0.18 μM) and low cytotoxicity (CC50 > 50 μM) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CLpro inhibitors and deserved further research.

Keywords

3CL(pro) inhibitor; Benzothiazolyl ketone; Peptidomimetics; Pharmacokinetic properties; SARS-CoV-2.

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