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

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.