2. Academic Validation
  3. N-acylbenzimidazoles as selective Acylators of the catalytic cystein of the coronavirus 3CL protease

N-acylbenzimidazoles as selective Acylators of the catalytic cystein of the coronavirus 3CL protease

  • Eur J Med Chem. 2024 Oct 5:276:116707. doi: 10.1016/j.ejmech.2024.116707.
Fatima-Zahra Chaibi 1,  Lucile Brier 1,  Paul Carré 1,  Valérie Landry 2,  Lowiese Desmarets 3,  Audrey Tarricone 4,  François-Xavier Cantrelle 5,  Danai Moschidi 5,  Adrien Herledan 2,  Alexandre Biela 1,  Fanny Bourgeois 1,  Chloé Ribes 1,  Sarah Ikherbane 1,  Mathilde Malessan 1,  Jean Dubuisson 3,  Sandrine Belouzard 4,  Xavier Hanoulle 5,  Florence Leroux 6,  Benoit Deprez 7,  Julie Charton 8
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 2 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France.
  • 3 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000, Lille, France.
  • 4 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000, Lille, France.
  • 5 CNRS, EMR9002 - BSI - Integrative Structural Biology, F-59000, Lille, France; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000, Lille, France.
  • 6 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000, Lille, France; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000, Lille, France.
  • 7 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000, Lille, France. Electronic address: benoit.deprez@univ-lille.fr.
  • 8 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000, Lille, France.
PMID: 39068863 DOI: 10.1016/j.ejmech.2024.116707
Abstract

The 3CL protease (3CLpro, Mpro) plays a key role in the replication of the SARS-CoV-2 and was validated as therapeutic target by the development and approval of specific Antiviral drugs (nirmatrelvir, ensitrelvir), inhibitors of this protease. Moreover, its high conservation within the coronavirus family renders it an attractive therapeutic target for the development of anti-coronavirus compounds with broad spectrum activity to control COVID-19 and future coronavirus diseases. Here we report on the design, synthesis and structure-activity relationships of a new series of small covalent reversible inhibitors of the SARS-CoV-2 3CLpro. As elucidated thanks to the X-Ray structure of some inhibitors with the 3CLpro, the mode of inhibition involves acylation of the thiol of the catalytic cysteine. The synthesis of 60 analogs led to the identification of compound 56 that inhibits the SARS-CoV-2 3CLpro with high potency (IC50 = 70 nM) and displays Antiviral activity in cells (EC50 = 3.1 μM). Notably, compound 56 inhibits the 3CLpro of three Other human coronaviruses and exhibit a good selectivity against two human cysteine proteases. These results demonstrate the potential of this electrophilic N-acylbenzimidazole series as a basis for further optimization.

Keywords

3CL(pro); Covalent reversible inhibitors; SARS-CoV-2.

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