Structure activity relationship-guided scaffold hopping for identification of novel thiadiazole derivatives as potent SARS-CoV-2 Mpro inhibitors

Abstract The ongoing COVID-19 pandemic has presented enormous challenges to worldwide healthcare systems, and effective therapeutic strategies must accompany mass vaccination efforts. In this context, Mpro (the main protease of SARS-CoV-2) is arguably one of the most promising molecular targets for antiviral drug development because it is responsible for processing viral polyproteins and replicating the virus. In this study, a rational design approach was employed to develop a novel series of thiadiazole-based derivatives as potential Mpro inhibitors. A total of compounds ( 5a–f , 9a–d , and 12a–j ) were synthesized through three systematically organized synthetic schemes. Each stage of the design strategy incorporated progressive structural modifications to establish a clear structure activity relationship (SAR) and enhance inhibitory potency. The synthesized compounds were evaluated for their in vitro inhibitory activity against SARS-CoV-2 Mpro. Some derivatives like 5b (IC 50 = 44.63 ± 1.20 µM), 12c (IC 50 = 39.25 ± 1.60 μM), 12a (IC 50 = 41.93 ± 1.90 μM), showed good inhibitory activity as compared to reference drug Nirmatrelvir (IC 50 = 58.4 ± 8.6 μM). Molecular docking analysis supported the experimental data by confirming stable binding of the synthesized compounds within the Mpro active site through key hydrogen-bonding and hydrophobic interactions.