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

Publication date: May 22, 2026

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 = 44. 63 +/- 1. 20 uM), 12c (IC = 39. 25 +/- 1. 60 μM), 12a (IC = 41. 93 +/- 1. 90 μM), showed good inhibitory activity as compared to reference drug Nirmatrelvir (IC = 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.

Semantics

Original Article