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.
Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Indoles/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/metabolism , Alanine/analogs & derivatives , Alanine/chemistry , Alanine/metabolism , Animals , Binding Sites , COVID-19/pathology , COVID-19/virology , Chlorocebus aethiops , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Humans , Indoles/chemical synthesis , Indoles/metabolism , Molecular Dynamics Simulation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/metabolism , Pyridines/chemistry , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Vero CellsABSTRACT
The virus SARS CoV-2, which causes the respiratory infection COVID-19, continues its spread across the world and to date has caused more than a million deaths. Although COVID-19 vaccine development appears to be progressing rapidly, scientists continue the search for different therapeutic options to treat this new illness. In this work, we synthesized five new 1-aryl-5-(3-azidopropyl)indol-4-ones and showed them to be potential inhibitors of the SARS CoV-2 main protease (3CLpro). The compounds were obtained in good overall yields and molecular docking indicated favorable binding with 3CLpro. In silico ADME/Tox profile of the new compounds were calculated using the SwissADME and pkCSM-pharmacokinetics web tools, and indicated adequate values of absorption, distribution and excretion, features related to bioavailability. Moreover, low values of toxicity were indicated for these compounds. And drug-likeness levels of the compounds were also predicted according to the Lipinski and Veber rules.