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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 (MPro), 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 MPro is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with (R)-carvone and (R)-pulegone thiosemicarbazones. The binding affinity and atomistic 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 MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG). 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 MPro biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC50 of 92.9 µM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future MPro inhibitors.

The absolute structure of the title compound was determined from the synthetic pathway and by resonant scattering. The compound is a new thia­zolidin-4-one derivative, prepared from (R)-thio­semicarbazone pulegone, and was isolated on crystallization from ethanol as the pure (3aS,6R)-diastereisomer., The title compound, C13H19N3OS, is a new thia­zolidin-4-one derivative prepared and isolated as the pure (3aS,6R)-diastereisomer from (R)-thio­semicarbazone pulegone. It crystallized with two independent mol­ecules (A and B) in the asymmetric unit. The compound is composed of a hexhydro­indazole ring system (viz. a five-membered di­hydro­pyrazole ring fused to a cyclo­hexyl ring) with a thia­zole-4-one ring system attached to one of the pyrazole N atoms (at position 2). The overall geometry of the two mol­ecules differs slightly, with the mean planes of the pyrazole and thia­zole rings being inclined to one another by 10.4 (1)° in mol­ecule A and 0.9 (1)° in mol­ecule B. In the crystal, the A and B mol­ecules are linked via C—H⋯O hydrogen bonds, forming slabs parallel to the ab plane. There are C—H⋯π inter­actions present within the layers, and between the layers, so forming a three-dimensional structure.