Investigating novel thiazolyl-indazole derivatives as scaffolds for SARS-CoV-2 M inhibitors.

COVID-19 is a global pandemic caused by infection with the SARS-CoV-2 virus. Remdesivir, a SARS-CoV-2 RNA polymerase inhibitor, is the only drug to have received widespread approval for treatment of COVID-19. The SARS-CoV-2 main protease enzyme (M), essential for viral replication and transcription, remains an active target in the search for new treatments. In this study, the ability of novel thiazolyl-indazole derivatives to inhibit M is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with ()-carvone, ()-pulegone and ()-menthone thiosemicarbazones. The binding affinity and binding interactions of each compound were evaluated through Schrödinger Glide docking, AMBER molecular dynamics simulations, and MM-GBSA free energy estimation, and these results were compared with similar calculations of M binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified M tight-binder X77. From these simulations, we can see that binding is driven by residue specific interactions such as π-stacking with His41, and S/π interactions with Met49 and Met165. The compounds were also experimentally evaluated in a M biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC of 92.9 ​μM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future M inhibitors.