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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, (R)-pulegone and (R)-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 MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified MPro 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 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 crystal structure and the conformation of the title compound, C22H27N3O7S, were determined from the synthetic pathway and by X-ray analysis. This compound is a new 4-thiazolidinone derivative prepared and isolated as pure product from thiosemicarbazone carvone. The molecule is built up from an oxothiazolidine ring tetrasubstituted by a methoxy–oxoethylidene, a maleate, an oxygen and a cyclohexylidene–hydrazone. The cyclohexylidene ring is statistically disordered over two positions, resulting in an inversion of configuration for the substituted carbon.

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.

The title compound, C11H19N3S, was prepared by the reaction of (R)-pulegone with thiosemicarbazide in acidic medium, using ethanol as solvent. The molecule is built up from fused six and five-membered rings. The six-membered ring adopts a chair conformation, while the five-membered ring displays an envelope conformation with the dimethyl-substituted C atom as the flap. The dihedral angle between the mean planes of the two rings is 20.35 (6)°. In the crystal, molecules are linked by N—H...N and N—H...S hydrogen bonds into chains running parallel to [100].