Development of 2-chloroquinoline based heterocyclic frameworks as dual inhibitors of SARS-CoV-2 M^Pro and PL^Pro.

ABSTRACT: Evolution of new variants of SARS-CoV-2 warrant the need for the continued efforts in identifying target-oriented new drugs. Dual targeting agents against M^Pro and PL^Pro not only overcome the incomplete efficacy but also the drug resistance, which is common problem. Since both these are cysteine proteases, we designed 2-chloroquinoline based molecules with additional imine moiety in the middle as possible nucleophilic warheads. In the first round of design and synthesis, three molecules (C3, C4 and C5) inhibited (Ki < 2 μM) only M^Pro by binding covalently to C145 and one molecule (C10) inhibited both the proteases non-covalently (Ki < 2 μM) with negligible cytotoxicity. Further conversion of the imine in C10 to azetidinone (C11) improved the potency against

SUBMITTER: Kattula B 

PROVIDER: S-EPMC10171901 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature