SARS-CoV-2 is the
causative agent behind the COVID-19
pandemic.
The main protease (Mpro, 3CLpro) of SARS-CoV-2
is a key enzyme that processes polyproteins translated from the viral
RNA. Mpro is therefore an attractive target for the design
of inhibitors that block viral replication. We report the diastereomeric
resolution of the previously designed SARS-CoV-2 Mpro α-ketoamide
inhibitor 13b. The pure (S,S,S)-diastereomer, 13b-K, displays an IC50 of 120 nM against the Mpro and EC50 values of 0.8–3.4 μM for
antiviral activity in different cell types. Crystal structures have
been elucidated for the Mpro complexes with each of the
major diastereomers, the active (S,S,S)-13b (13b-K), and the nearly inactive (R,S,S)-13b
(13b-H); results for the latter reveal a novel binding
mode. Pharmacokinetic studies show good levels of 13b-K after inhalative as well as after peroral administration. The active
inhibitor (13b-K) is a promising candidate for further
development as an antiviral treatment for COVID-19.
Intermolecular photochemical [2 + 21 cycloaddition of a During part of a program involving the use of organic variety of alken-and alkyn-3-01s with photochemistry in the total synthesis of cyclooctane containing 3,4,5,6-tetrahydrophthalic anhydride (THPA) and the related
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