Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure-Activity Relationship, and X-ray Structural Studies

  • J Med Chem. 2021 Oct 14;64(19):14702-14714. doi: 10.1021/acs.jmedchem.1c01214.
Arun K Ghosh  1 ,  Jakka Raghavaiah  1 ,  Dana Shahabi  1 ,  Monika Yadav  1 ,  Brandon J Anson  2 ,  Emma K Lendy  3 ,  Shin-Ichiro Hattori  4 ,  Nobuyo Higashi-Kuwata  4 ,  Hiroaki Mitsuya  5  6  4 ,  Andrew D Mesecar  2  3
Affiliations
  • 1. Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • 2. Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, United States.
  • 3. Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • 4. Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku, Tokyo 162-8655, Japan.
  • 5. Department of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
  • 6. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland 20892, United States.
PMID: 34528437 DOI: 10.1021/acs.jmedchem.1c01214
Abstract

Here, we report the synthesis, structure-activity relationship studies, enzyme inhibition, Antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class of SARS-CoV-2 chymotrypsin-like Protease Inhibitors. Compound 1 exhibited a SARS-CoV-2 3CLpro inhibitory IC50 value of 250 nM and an Antiviral EC50 value of 2.8 μM in VeroE6 cells. Remdesivir, an RNA-dependent RNA polymerase inhibitor, showed an Antiviral EC50 value of 1.2 μM in the same assay. Compound 1 showed comparable Antiviral activity with remdesivir in immunocytochemistry assays. Compound 7d with an N-allyl derivative showed the most potent enzyme inhibitory IC50 value of 73 nM. To obtain molecular insight into the binding properties of these molecules, X-ray crystal structures of compounds 2, 7b, and 9d-bound to SARS-CoV 3CLpro were determined, and their binding properties were compared.

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