title: Importance of cytochromes in cyclization reactions: quantum chemical study on a model reaction of proguanil to cycloguanil.
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.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali), 160 062, Punjab, India.
authors.forename: Minhajul
authors.initials: M
authors.lastname: Arfeen
authors.forename: Dhilon S
authors.initials: DS
authors.lastname: Patel
authors.forename: Sheenu
authors.initials: S
authors.lastname: Abbat
authors.forename: Nikhil
authors.initials: N
authors.lastname: Taxak
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Bharatam
mesh_terms: D003500:Cyclization; D003580:Cytochromes / Q000737:chemistry*; D008956:Models, Chemical; D002727:Proguanil / Q000737:chemistry*; D011789:Quantum Theory; D014227:Triazines / Q000737:chemistry*
chemical_list: D003580:Cytochromes; D014227:Triazines; C026009:cycloguanil; D002727:Proguanil
keywords: DFT; cyclization reaction; cycloguanil; cytochrome; molecular mechanism; proguanil