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

• Published in: Journal of Medicinal Chemistry Vol. 64; no. 19; pp. 14702 - 14714
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.10.2021; American Chemical Society (ACS); Amer Chemical Soc
• Subjects: 1 </ b; 250 nm; 50 </ sub; 73 nm; 7d </ b; 8 μm; Adenosine Monophosphate; Alanine; Animals; antiviral activity; antiviral ec; antiviral efficacy; binding properties; Binding Sites; Biochemistry; Biophysics; Biotechnology; Cancer; Chemical Sciences not elsewhere classified; Chemistry, Medicinal; Chlorocebus aethiops; Coronavirus 3C Proteases; COVID-19; Crystallography, X-Ray; enzyme inhibition; Humans; immunocytochemistry assays; indole chloropyridinyl ester; Indoles; Infectious Diseases; Information Systems not elsewhere classified; Life Sciences & Biomedicine; like protease inhibitors; Molecular Dynamics Simulation; n; obtain molecular insight; Pharmacology; Pharmacology & Pharmacy; potent class; Protease Inhibitors; Pyridines; ray crystal structures; ray crystallographic studies; SARS-CoV-2; Science & Technology; Structure-Activity Relationship; Vero Cells; veroe6 cells; Virology; DESIGN; REPLICATION; SERIES; PAPAIN-LIKE; BIOLOGICAL EVALUATION; OPTIMIZATION; SARS-CORONAVIRUS; DISCOVERY
• DOI: 10.1021/acs.jmedchem.1c01214
• ISSN: 0022-2623; 1520-4804

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.