Ionic liquids and lysosomotropic detergents as inhibitors of the SARS-CoV-2 main protease: QSAR modeling, synthesis and biological testing.

SARS-CoV-2 infection is highly contagious, prompting the World Health Organization to classify it as a global public health emergency. The virus has numerous potential hosts, which complicates efforts for effective prevention, diagnosis, and treatment. Consequently, the development of innovative antiviral agents targeting SARS-CoV-2 is essential to mitigate complications and reduce mortality rates associated with COVID-19. The main protease (Mpro), also known as 3CLpro, is a key target for drug development because of its critical role in processing viral polyproteins and its evolutionary conservation among coronaviruses, making it a promising candidate for therapeutic intervention against SARS-CoV-2. In this study, a multitask machine learning approach was employed to evaluate the antiviral effectiveness of different chemical compounds against Mpro, using resources from the publicly available Online Chemical Database and Modeling Environment. The dataset for QSAR modeling consisted of 2844 compounds with antiviral activity measured as the EC50 against SARS-CoV-2 and inhibitory activity (IC50) against the major protease of the virus. The predictive performance of the QSAR models was rigorously validated using both cross-validation and external test sets. Thirteen compounds, identified by the QSAR models as having high anti-Mpro activity, were subsequently tested in vitro as protease inhibitors using a fluorescence assay. The six most active compounds were further examined through counter screening and selective screening using trypsin and papain. The highest inhibitory activity was observed in an ionic liquid derived from pyridine (16), which exhibited an IC50 of 25.15 μM, alongside compounds 6 and 7, which are based on imidazole, both of which demonstrated an IC50 of 26.2 μM. In light of the developed in silico activity model and the outcomes of the in vitro investigation of anti-Mpro activity, these compounds are promising candidates for further research as potential anti-SARS-CoV-2 agents.