UCI-1

The global outbreak of COVID-19, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has resulted in over 774 million cases and 7 million deaths worldwide since January 2020. Although widespread vaccination has been instrumental in reducing transmission and disease severity, there is a persistent and urgent need for effective treatments. This has made the virus's main protease (M^pro), a key enzyme in its replication cycle, a leading target for drug development. In the current research work, a schematic strategy was utilized to design, synthesize and screen the biological activity of newly prepared thiadiazole derivatives (5a-f, 9a-d and 12a-j) against M^pro as SARS-CoV-2 inhibitors. The research plan was organized into three schemes, where every step advanced from the outcome of the former one to create a clear structure activity relationship (SAR) and successively optimize biological activity. Specifically compounds 12c (IC₅₀ = 0.03077 μM), and 12a (IC₅₀ = 0.03356 μM) exhibited excellent inhibitory potency as compared to reference drug Nirmatrelvir (IC₅₀ = 0.05855 μM). The Molecular docking study further validated the experimental results revealing that the synthesized molecules interacted strongly with the SARS-CoV-2 M^pro active site via multiple hydrogen bonds and hydrophobic interactions with important catalytic residues, resulting in stable enzyme inhibitor complexes consistent with the in-vitro results. Nevertheless, further cell-based antiviral studies are required to validate the ability of these compounds to suppress SARS-CoV-2 replication under physiological conditions. However, further selectivity studies against human proteases are necessary to evaluate potential off-target effects and safety profiles.