Cycloguanil (hydrochloride)

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

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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 hydroxylase. Br. 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 resistance. Proc. Natl. Acad. Sci. USA 87(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 falciparum. J. 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 action. Ann. 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 dichlorguanide. Proc. Soc. Exp. Biol. Med. 80(2), 367-370 (1952).