Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL^pro Main Protease

• Main Authors: Barbara Herlah (Author), Andrej Hoivik (Author), Luka Jamšek (Author), Katja Valjavec (Author), Norio Yamamoto (Author), Tyuji Hoshino (Author), Krištof Kranjc (Author), Andrej Perdih (Author)
• Format: Book
• Published: MDPI AG, 2022-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph15050539; 1424-8247
• Keywords: bicyclo[2.2.2]octenes; molecular scaffolds; SARS-CoV-2; 3CL^pro main protease; COVID-19 antiviral drugs; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 15, Iss 5, p 539 (2022)

The emergence of SARS-CoV-2, responsible for the global COVID-19 pandemic, requires the rapid development of novel antiviral drugs that would contribute to an effective treatment alongside vaccines. Drug repurposing and development of new molecules targeting numerous viral targets have already led to promising drug candidates. To this end, versatile molecular scaffolds with high functionalization capabilities play a key role. Starting with the clinically used conformationally flexible HIV-1 protease inhibitors that inhibit replication of SARS-CoV-2 and bind major protease 3CL^pro, we designed and synthesized a series of rigid bicyclo[2.2.2]octenes fused to <i>N</i>-substituted succinimides to test whether this core scaffold could support the development of non-covalent 3CL^pro inhibitors. Inhibition assays confirmed that some compounds can inhibit the SARS-CoV-2 main protease; the most promising compound <b>11a</b> inhibited 3CL^pro in micromolar range (IC₅₀ = 102.2 μM). Molecular simulations of the target-ligand complex in conjunction with dynophore analyses and endpoint free energy calculations provide additional insight and first recommendations for future optimization. The fused bicyclo[2.2.2]octenes can be used as a new potential starting point in the development of non-covalent SARS-CoV-2 3CL^pro protease inhibitors and the study also substantiates the potential of this versatile scaffold for the development of biologically active molecules.