Importance of substituents in ring opening: a DFT study on a model reaction of thiazole to thioamide.

Thiazole ring is an important active molecular skeleton of drugs. Thiazole in natural products and drugs are usually harmlessly eliminated. However, hepatotoxic reactions may occur due to the biological activation of thiazole to produce reactive thioamide. A typical example is hepatotoxic sudoxicam and safety meloxicam. The only structural difference between them is a methyl group on C5 position of thiazole in meloxicam. The molecular basis for the difference remains unknown and the bioactivation mechanism of the thiazole ring is still obscure. Quantum chemical calculations were performed to elucidate the activation mechanism of the thiazole ring under P450 catalysis, and the influence of the substituents on the activation pathways of thiazole ring was also studied. The calculated results show that the activation of thiazole is closely related to the substituents on the thiazole and spin state of Cpd I. The thiazole and substituted thiazole directly open the ring when catalyzed by doublet spin state Cpd I that catalyzed by the quartet spin state Cpd I can open the ring directly or indirectly, which is related to the substituents. Thiazoles modified with electron-donating substituents mainly undergo direct ring opening, while thiazoles modified with electron-withdrawing groups or weak electron-donating groups mainly undergo indirect ring-opening process accompanied by intermediate formation. The research results laid the foundation for the design of thiazole ring drugs, and also laid a theoretical foundation for the study of reducing the toxicity of thiazole ring drugs.