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

Bai, Xue; Qin, Dan; Yang, Lijun

doi:10.1007/s00894-021-04704-5

Cited by 1 publication

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“…Therefore, discussing the metabolic mechanisms that occur at the methyl, C4, and C5 positions is of great significance to clarify the reasons for the differences in the toxicity of the two drugs. The mechanism of thiazole metabolism explored by density functional theory (DFT) shows that there are several ring‐opening processes for thiazole, [ 16 ] which are affected by factors such as the spin state of Compound I (Cpd I), properties, and positions of substituents on thiazole. The charges on C4 and C5 of thiazole are both negative (Table 1), do these reaction centers affect metabolic processes and products?…”

Section: Introductionmentioning

confidence: 99%

Theoretical study of thiazole activation in sudoxicam and meloxicam: Reaction center, biotransformation, and methyl effects

Qin

Yang

2022

J Chinese Chemical Soc

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The molecular mechanism of sudoxicam and meloxicam metabolism to thioamide is clarified based on the results of quantum chemistry calculations. The two drugs are first activated to generate carbonyl intermediate 5‐PC. When the reaction site is on C5 of the thiazole ring, 5‐PC is directly obtained; when the reaction site is on C4, metabolite epoxide is easily isomerized to give 5‐PC instead of hydrolysis to glycols. 5‐PC is an important intermediate, which is further metabolized to generate thioamide. The molecular docking experiments clarify the reasons for the difference in hepatotoxicity of two drugs caused by methyl groups. Compared with close distance between Fe and the thiazole ring in sudoxicam, the additional methyl group in meloxicam is more close to the Fe(III)‐heme moiety, which suppresses the bioactivation of the thiazole ring. The position of methyl binding in the cytochrome P450 pocket determines the activation difference of thiazole in meloxicam and sudoxicam. The study provides detailed molecular mechanisms for the differences in metabolism and toxicity of the two drugs and lays the foundations for drug design and drug modification.

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Section: Introductionmentioning

confidence: 99%