Cycloguanil-d6 (hydrochloride)

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; K_is = 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 µg/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)