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 3CLpro Main Protease

Barbara Herlah; Andrej Hoivik; Luka Jamšek; Katja Valjavec; Norio Yamamoto; Tyuji Hoshino; Krištof Kranjc; Andrej Perdih

doi:10.3390/ph15050539

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

Pharmaceuticals (Basel). 2022 Apr 27;15(5):539. doi: 10.3390/ph15050539.

Authors

Barbara Herlah^{1

2}, Andrej Hoivik³, Luka Jamšek³, Katja Valjavec¹, Norio Yamamoto⁴, Tyuji Hoshino⁵, Krištof Kranjc³, Andrej Perdih^{1

2}

Affiliations

¹ National Institute of Chemistry, Hajdrihova ulica 19, SI-1000 Ljubljana, Slovenia.
² Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
³ Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia.
⁴ Department of Microbiology, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan.
⁵ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Chiba, Japan.

Abstract

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 N-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 11a 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.

Keywords: 3CLpro main protease; COVID-19 antiviral drugs; SARS-CoV-2; bicyclo[2.2.2]octenes; molecular scaffolds.

Abstract

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