Cycloguanil-d6 is intended for use as an internal standard for the quantification of cycloguanil by GC- or LC-MS. Cycloguanil is the active metabolite of the antimalarial prodrug proguanil.1 Cycloguanil is formed from proguanil by the cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A in human liver microsomes. It is an inhibitor of dihydrofolate reductase (DHFR; Kis = 1.5 and 0.79 nM for the P. falciparum and P. berghei enzymes, respectively).2,3 It is active against ten P. falciparum field isolates (IC50s = 0.12-1,400 ?g/ml).2 Cycloguanil reduces parasitemia in a mouse model of P. berghei infection (ED50 = 2 mg/kg).4 It also reduces parasitemia in a rhesus monkey model of P. cynomolgi infection when administered at a dose of 0.3 mg/kg.5
1.Birkett, D.J., Rees, D., Anderson, T., et al.In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylaseBr. J. Clin. Pharmacol.37(5)413-420(1994) 2.Foote, S.J., Galatis, D., and Cowman, A.F.Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistanceProc. Natl. Acad. Sci. USA87(8)3014-3017(1990) 3.Yuthavong, Y., Vilaivan, T., Chareonsethakul, N., et al.Development of a lead inhibitor for the A16V+S108T mutant of dihydrofolate reductase from the cycloguanil-resistant strain (T9/94) of Plasmodium falciparumJ. Med. Chem.43(14)2738-2744(2000) 4.Knight, D.J., and Peters, W.The antimalarial activity of N-benzyloxydihydrotriazines. I. The activity of clociguanil (BRL 50216) against rodent malaria, and studies on its mode of actionAnn. Trop. Med. Parasitol.74(4)393-404(1980) 5.Schmidt, L.H., Loo, T.L., Fradkin, R., et al.Antimalarial activities of triazine metabolites of chlorguanide and dichlorguanideProc. Soc. Exp. Biol. Med.80(2)367-370(1952)