Development of potent and effective SARS-CoV-2 main protease inhibitors based on maleimide analogs for the potential treatment of COVID-19

Abstract

In the present work, we report a new series of potent SARS-CoV-2 Main Protease (Mpro) inhibitors based on maleimide derivatives. The inhibitory activities were tested in an enzymatic assay using recombinant Mpro (3CL Protease from coronavirus SARS-CoV-2). Within the set of new Mpro inhibitors, 6e demonstrated the highest activity in the enzymatic assay with an IC₅₀ value of 8.52 ± 0.44 µM. The IC₅₀ value for Nirmatrelvir (PF-07321332, used as a reference) was 0.84 ± 0.37 µM. The cytotoxic properties were determined in the MTT assay using MRC-5 and HEK-293 cell lines. In the course of the investigation, we found that the newly obtained maleimide derivatives are not substantially cytotoxic (IC₅₀ values for most compounds were above 200 µM).

Keywords: COVID-19; Coronavirus SARS-CoV-2; SARS-CoV-2 main protease mpro inhibitors; maleimide derivatives.

Figure 1.

Chemical structures of SARS-CoV-2 Mpro inhibitors approved for clinical use for the treatment of COVID-19.

Scheme 1.

Synthesis of dipeptide, tripeptide and tetrapeptide derivatives of 1–(2-hydroxyethyl)-1H-pyrrole-2,5-dione and 1–(3-hydroxypropyl)-1H-pyrrole-2,5-dione (6a-6s).

Scheme 2.

Synthesis of trifluoroacetate derivatives 6g’, 6h’, 6m’, and 6n’.

Scheme 3.

Synthesis of Ac-l-Thz-Gly-2CSucc derivative (Ref1).