Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity
Angelo Oneto, Ghazl Al Hamwi, Laura Schäkel, Nadine Krüger, Katharina Sylvester, Marvin Petry, Rasha Abu Shamleh, Thanigaimalai Pillaiyar, Tobias Claff, Anke C. Schiedel, Norbert Sträter, Michael Gütschow, Christa Elisabeth Müller · Journal of Medicinal Chemistry · 2024
SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing a variety of substituents as irreversible inhibitors of the main viral protease (M pro ). Altogether, 55 benzoyl chloro/bromo-pyridyl esters were synthesized, with broad variation of the substitution pattern on the benzoyl moiety. A workflow was employed for multiparametric optimization, including M pro inhibition assays of SARS-CoV-2 and related pathogenic coronaviruses, the duration of enzyme inhibition, the compounds’ stability versus glutathione, cytotoxicity, and antiviral activity. Several compounds showed IC 50 values in the low nanomolar range, k inact / K i values of >100,000 M –1 s –1 and high antiviral activity. High-resolution X-ray cocrystal structures indicated an important role of ortho -fluorobenzoyl substitution, forming a water network that stabilizes the inhibitor-bound enzyme. The most potent antiviral compound was the p -ethoxy- o -fluorobenzoyl chloropyridyl ester (PSB-21110, 29b, MW 296 g/mol; EC 50 2.68 nM), which may serve as a lead structure for broad-spectrum anticoronaviral therapeutics.