Importance of cytochromes in cyclization reactions: quantum chemical study on a model reaction of proguanil to cycloguanil.
J Comput Chem
; 35(28): 2047-55, 2014 Oct 30.
Article
em En
| MEDLINE
| ID: mdl-25196060
ABSTRACT
Proguanil, an anti-malarial prodrug, undergoes cytochrome P450 catalyzed biotransformation to the pharmacologically active triazine metabolite (cycloguanil), which inhibits plasmodial dihydrofolate reductase. This cyclization is catalyzed by CYP2C19 and many anti-malarial lead compounds are being designed and synthesized to exploit this pathway. Quantum chemical calculations were performed using the model species (Cpd I for active species of cytochrome and N4-isopropyl-N6-methylbiguanide for proguanil) to elucidate the mechanism of the cyclization pathway. The overall reaction involves the loss of a water molecule, and is exothermic by approximately 55 kcal/mol, and involves a barrier of approximately 17 kcal/mol. The plausible reaction pathway involves the initial H-radical abstraction from the isopropyl group by Cpd I, followed by two alternative paths- (i) oxygen rebound to provide hydroxyl derivative and (ii) loss of additional H-radical to yield 1,3,5-triazatriene, which undergoes cyclization. This study helped in understanding the role of the active species of cytochromes in this important cyclization reaction.
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Base de dados:
MEDLINE
Assunto principal:
Teoria Quântica
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Triazinas
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Proguanil
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Citocromos
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Modelos Químicos
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article