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Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure-Activity Relationship, and X-ray Structural Studies.
Ghosh, Arun K; Raghavaiah, Jakka; Shahabi, Dana; Yadav, Monika; Anson, Brandon J; Lendy, Emma K; Hattori, Shin-Ichiro; Higashi-Kuwata, Nobuyo; Mitsuya, Hiroaki; Mesecar, Andrew D.
  • Ghosh AK; Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • Raghavaiah J; Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • Shahabi D; Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • Yadav M; Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • Anson BJ; Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, United States.
  • Lendy EK; Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907, United States.
  • Hattori SI; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku, Tokyo 162-8655, Japan.
  • Higashi-Kuwata N; Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Shinjuku, Tokyo 162-8655, Japan.
  • Mitsuya H; Department of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.
  • Mesecar AD; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland 20892, United States.
J Med Chem ; 64(19): 14702-14714, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1412442
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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 / Indoles Limits: Animals / Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.1c01214

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protease Inhibitors / Coronavirus 3C Proteases / SARS-CoV-2 / Indoles Limits: Animals / Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.1c01214