Disease relevance of NSC 3074

• Increasing resistance of Plasmodium falciparum malaria parasites to chloroquine and the dihydrofolate reductase (DHFR) inhibitors pyrimethamine and cycloguanil have sparked renewed interest in the antimalarial drugs WR99210 and proguanil, the cycloguanil precursor [1].
• Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil [2].
• As part of the search for new antimalarial drugs, a screening program was developed using sensitive and chlorguanide triazine (CGT, cycloguanil) resistant strains of the folate-requiring bacteria, Streptococcus faecium durans, Lactobacillus casei, and Pediococcus cerevisiae [3].
• The Cmax and AUCo-alpha of the active metabolite cycloguanil was significantly decreased (P < 0.05) in both the healthy subjects and in the peptic ulcer patients [4].
• The proguanil to cycloguanil ratio was assessed in 10 cases each of know severe and mild psoriasis [5].

High impact information on NSC 3074

• Instead of the known serine-to-asparagine change at position 108 that is important in pyrimethamine resistance, a serine-to-threonine change at the same position is found in cycloguanil-resistant isolates along with an alanine-to-valine change at position 16 [6].
• A biochemical and genetic model for parasite resistance to antifolates. Toxoplasma gondii provides insights into pyrimethamine and cycloguanil resistance in Plasmodium falciparum [7].
• It also confirms that CYP2C19 genotype and phenotype predicts cycloguanil formation [8].
• Chloroguanide and its two metabolites cycloguanil and 4-chlorphenylbiguanide in plasma and in urine were assayed by means of HPLC [9].
• These findings confirm that the bioactivation of chloroguanide to cycloguanil cosegregates with the genetically determined activity of the CYP2C family [10].

Chemical compound and disease context of NSC 3074

• It was found that leucocytes treated with mefloquine, proguanil and cycloguanil at concentrations higher than 0.5 mg/litre showed reduced phagocytic activity against Staphylococcus aureus [11].
• OBJECTIVE: To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil [12].

Biological context of NSC 3074

• These results reflect the distinct structures of pyrimethamine and cycloguanil and suggest fine differences in binding within the active site cavity of DHFR [13].
• OBJECTIVE: We investigated the impact of CYP2C19 genotype and phenotype on chloroguanide (INN, proguanil) metabolism to its metabolites cycloguanil and 4-chlorophenylbiguanide [8].
• We confirm previously available data showing that parasites harboring a point mutation from Ser108 to Asn present a decrease in susceptibility to cycloguanil (the active metabolite of proguanil), and we show that mutations in codons 51 and 59 appear to modulate the level of resistance to cycloguanil [14].
• Thirteen and 18 isolates were resistant to pyrimethamine (mean IC50 9,440 nM) and cycloguanil (mean IC50 2,030 nM), respectively [15].
• METHODS: The kinetics of the formation of 4'-hydroxymephenytoin and cycloguanil in human liver microsomes from 10 liver samples were determined, and inhibition of formation was studied using specific chemical inhibitors and monoclonal antibodies directed towards specific CYP450 isoforms [16].

Anatomical context of NSC 3074

• With pyrimethamine, proguanil, cycloguanil, primaquine, and 2 of its analogues (WR242511 and WR238605), marked inhibition of schizont formation could be achieved at concentrations below those causing a cytotoxic effect on the host hepatocytes [17].
• Higher concentrations of cycloguanil, corresponding to intralymphocytic levels in clinical practice, permanently suppressed the growth of lymphocytes [18].

Associations of NSC 3074 with other chemical compounds

• Although the human enzyme also resulted in greater resistance to cycloguanil, no decrease was found in the level of susceptibility of transformed parasites to proguanil, thus providing evidence of intrinsic activity of this parent compound against a target other than DHFR [1].
• The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine-, cycloguanil-, and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys [19].
• Development of a lead inhibitor for the A16V+S108T mutant of dihydrofolate reductase from the cycloguanil-resistant strain (T9/94) of Plasmodium falciparum [20].
• The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dihydrofolate reductase (DHFR) is a key mutant responsible for cycloguanil-resistant malaria due to steric interaction between Val-16 and one of the C-2 methyl groups of cycloguanil [20].
• At a proguanil concentration of 20 microM, omeprazole at 10 microM inhibited cycloguanil formation in vitro by 47 +/- 59% [21].

Gene context of NSC 3074

• CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment [22].
• Cycloguanil formation activity did not correlate with immunoreactive CYP3A4 content or with CYP3A4 activity, as measured by testosterone 6beta-hydroxylation, suggesting that CYP3A4 plays a limited role in cycloguanil formation [21].
• Pyrimethamine and cycloguanil are competitive inhibitors of the Plasmodium enzyme dihydrofolate reductase (DHFR) [23].
• 1. The activation of proguanil to cycloguanil by human liver microsomes was studied to define the cytochrome P450 (CYP) isoforms involved in this reaction [24].
• Point mutations in the dihydrofolate reductase and dihydropteroate synthetase genes and in vitro susceptibility to pyrimethamine and cycloguanil of Plasmodium falciparum isolates from Papua New Guinea [25].

Analytical, diagnostic and therapeutic context of NSC 3074

• High-performance liquid chromatography of proguanil, cycloguanil and 4-chlorophenylbiguanide using hydrophobic pairing ion and its application to serum assay [26].
• A sensitive bioassay for serum cycloguanil using Plasmodium falciparum in vitro [27].
• Although high levels of parasite resistance to cycloguanil were probably responsible for the poor response to proguanil treatment, the inability of Thai EM and PM patients to produce cycloguanil may have also contributed to the treatment outcome [28].
• Proguanil and cycloguanil concentrations were measured by h.p.l.c. PCR was employed for CYP2C19 genotyping [29].
• The ex vivo antimalarial activity of plasma samples obtained from 20 healthy Caucasian volunteers following daily proguanil (200 mg) plus dapsone (8 mg) for malaria chemoprophylaxis inhibited five cycloguanil-resistant Thai isolates of Plasmodium falciparum [30].

References