1. Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure-Activity Relationship, and X-ray Structural Studies
- Author
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Brandon J. Anson, Dana Shahabi, Emma K. Lendy, Andrew D. Mesecar, Monika Yadav, Hiroaki Mitsuya, Jakka Raghavaiah, Nobuyo Higashi-Kuwata, Arun K. Ghosh, and Shin-ichiro Hattori
- Subjects
Indoles ,Stereochemistry ,Pyridines ,medicine.medical_treatment ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,Article ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Chlorocebus aethiops ,medicine ,Structure–activity relationship ,Animals ,Humans ,Protease Inhibitors ,Carboxylate ,Binding site ,IC50 ,Vero Cells ,Coronavirus 3C Proteases ,Indole test ,Protease ,Alanine ,Binding Sites ,Chemistry ,SARS-CoV-2 ,COVID-19 ,Adenosine Monophosphate ,RNA Polymerase Inhibitor ,Vero cell ,Molecular Medicine - 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.
- Published
- 2021