No abstract

The reaction mechanism of cytochrome P450‐mediated intramolecular cyclization of 2‐aminoamide compounds to imidazolinone was studied by density functional theory. The cyclization reaction involves three steps: hydrogen abstraction, dehydration of intermediates to zwitterions and final ring closure. Interestingly, high spin (HS) state P450‐catalyzed dehydration exhibits a mechanism distinct from conventional processes such as in low spin state. In HS pathways, the hydroxyl group after hydrogen abstraction does not rebound but produce an intermediate, which makes the second hydrogen abstraction regioselective. Regioselectivity leads to diverse intermediates and mechanisms to zwitterion, which implies different functions of the high and low spin states P450. The alkylamine nitrogen and amide group are key groups to enables regioselectivity of in HS pathway. Small changes of molecular structure can affect the molecular transformation process, indicating the complex regulation of electronic state to reaction process. The results lay the theoretical basis for the regioselectivity determined by P450 enzyme and substrate structure together. The research establishes a foundation for the drug design, drug metabolite, and synthesis of nitrogen‐containing heterocyclic drugs.

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.