Cycloguanil

Reaction of p-chloroaniline with dicyanamide affords the biguan-ide, 182. This is condensed immediately with acetone to form the aminal cycloguanil (183). The compound is usually used as a salt with pamoic acid (184). 

Proguanil appears to have a dual activity. Part of it is metabolized to cycloguanil, which subsequently inhibits the protozaon dihydrofolate reduc-tase/thymidylate synthase (DHFR/TS) (Fig. 4). In addition, the native form, proguanil itself, exerts a potent antimalarial activity, especially in combination with other antimalarial drugs. The target of proguanil is unknown. 

Cycloguanil, 281 Cyclomethycaine, 14 Cyclopal, 269, 270 Cyclopentamine, 37 Cyclopenthiazide, 358 Cyclopentolate, 92 Cyclopropylcarbynyl-homoallyl rearrangement, 31, 151, 182 Cyclopyrazolate, 92 3,5-Cyclosteroid, 182 Cy do thiazide, 358 Cycrimine, 47 Cyproheptadine, 151... 

It is slowly absorbed orally with peak plasma levels about 4 hours after dosing. Its protein binding is about 75%. It is metabolized in the liver to its tri-azine metabolite, the active compound cycloguanil, with an elimination half-life of on average 16 hours, however, with a wide interindividual variation. It is excreted in urine and faeces as unchanged drug and metabolites. 

Chloroguanide hydrochloride (Paludrine) is activated to a triazine metabolite, cycloguanil, which also interferes with parasite folic acid synthesis. It is a dihydrofolate reductase inhibitor that is used for the prophylaxis of malaria caused by all susceptible strains of plasmodia. Chloroguanide is rapidly absorbed from the gas-... 

Lipophilic groups that are not easily hydrolyzed are used extensively for depot preparations, which liberate the active drug molecule slowly, for a period of days or weeks. Steroid hormone palmitates and pamoates, and antimalarial esters (e.g., cycloguanil pamoate, 3.29), can deliver the active drugs over a prolonged time cycloguanil, for example, is released over a period of several months. This can he a great convenience for the patient, especially in areas with remote medical facilities. 

It is slowly but adequately absorbed from the GI tract. It is metabolised in the liver to the active metabolite cycloguanil. 

Pyrimidines have been extensively smdied as a source for antibacterial and antiparasitic agents that act as folate reductase inhibitors (see, for example, pyrimethamine [38-5]). This activity is maintained in compounds that incorporate an additional ring of nitrogen. A partly reduced 1,3,5 triazine, cycloguanil (89-4), shows... 

The dihydrotriazines are of interest because of their antimalarial activity, and their potential as cancer chemotherapeutic drugs (see Section 2.20.5.10). The X-ray crystallographic analysis of the antimalarial drug cycloguanil (12) (as the hydrochloride salt) has... 

Of interest is a recently described yeast-based, nutrient-dependent viability screen for inhibitors of protozoal dihydrofolate reductase (DHFR) [43,44], Antiprotozoal activity of DHFR inhibitors is well known, and DHFR- yeast complemented with the DHFR gene derived from the malaria parasite P. falciparum have been used to characterize the molecular pharmacology of resistance to the antimalarial DHFR inhibitors pyrimethamine and cycloguanil [45,46], The subsequent development of a screen was based on the demonstration that the protozoal... 

Ward SA, Watkins WM, Mberu E, et al. Inter-subject variability in the metabolism of proguanil to the active metabolite cycloguanil in man. Br J Clin Pharmacol 1989 27 781-787. 

Funck-Brentano C, Bosco O, Jacqz-Aigrain E, et al. Relation between chlor-oguanide bioactivation to cycloguanil and the genetically determined metabolism of mephenytoin in humans. Clin Pharmacol Ther 1992 51 507-512. 

Birkett DJ, Rees D, Andersson 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 1994 37 413 -20. 

Novartis Malaria Data from Gamo et al. (14), P. falciparum strains 3d7 (drug-susceptible), and W2 (chloroquine-, quinine-, pyrimethamine-, cycloguanil-, and sulfadoxine-resistant), obtained from MR4, were tested in an erythrocyte-based infection assay for susceptibility to inhibition of proliferation by selected compounds. 5,695... 

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