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Cycloguanil is a dihydrofolate reductase inhibitor,^[1] and is a metabolite of the antimalarial drug proguanil; its formation in vivo has been thought to be primarily responsible for the antimalarial activity of proguanil.^[2] However, more recent work has indicated that, while proguanil is synergistic with the drug atovaquone (as in the combination Malarone), cycloguanil is in fact antagonistic to the effects of atovaquone, suggesting that, unlike cycloguanil, proguanil may have an alternative mechanism of antimalarial action besides dihydrofolate reductase inhibition.^[3]

Although cycloguanil is not currently in general use as an antimalarial, the continuing development of resistance to current antimalarial drugs has led to renewed interest in studying the use of cycloguanil in combination with other drugs.^[4]

References

^ Srivastava IK, Vaidya AB; Vaidya (June 1999). "A mechanism for the synergistic antimalarial action of atovaquone and proguanil". Antimicrob. Agents Chemother. 43 (6): 1334–9. PMC 89274. PMID 10348748.
^ Watkins, W. S.; Sixsmith, D. G.; Chulay, J. D. (Jun 1984). "The activity of proguanil and its metabolites, cycloguanil and p-chlorophenylbiguanide, against Plasmodium falciparum in vitro" (Free full text). Annals of Tropical Medicine and Parasitology 78 (3): 273–278. ISSN 0003-4983. PMID 6385887.
^ Thapar, M. G.; Gupta, S.; Spindler, C.; Wernsdorfer, W. H.; Björkman, A. (May 2003). "Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitro". Transactions of the Royal Society of Tropical Medicine and Hygiene 97 (3): 331–337. doi:10.1016/S0035-9203(03)90162-3. ISSN 0035-9203. PMID 15228254.
^ Walzer, P. ; F.; Foy, J.; Steele, P.; White, M. (Jul 1993). "Synergistic combinations of Ro 11-8958 and other dihydrofolate reductase inhibitors with sulfamethoxazole and dapsone for therapy of experimental pneumocystosis". Antimicrobial Agents and Chemotherapy 37 (7): 1436–1443. doi:10.1128/AAC.37.7.1436. ISSN 0066-4804. PMC 187990. PMID 8363372.

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UpToDate Contents

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1. 抗マラリア剤：概要 antimalarial drugs an overview

English Journal

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target.

Yuthavong Y, Tarnchompoo B, Vilaivan T, Chitnumsub P, Kamchonwongpaisan S, Charman SA, McLennan DN, White KL, Vivas L, Bongard E, Thongphanchang C, Taweechai S, Vanichtanankul J, Rattanajak R, Arwon U, Fantauzzi P, Yuvaniyama J, Charman WN, Matthews D.SourceBIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand. yongyuth@biotec.or.th
Proceedings of the National Academy of Sciences of the United States of America.Proc Natl Acad Sci U S A.2012 Oct 16;109(42):16823-8. doi: 10.1073/pnas.1204556109. Epub 2012 Oct 3.
Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures
PMID 23035243

Combined spatial limitation around residues 16 and 108 of Plasmodium falciparum dihydrofolate reductase explains resistance to cycloguanil.

Vanichtanankul J, Taweechai S, Uttamapinant C, Chitnumsub P, Vilaivan T, Yuthavong Y, Kamchonwongpaisan S.SourceNational Centre for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Klong Luang, Pathumthani, Thailand.
Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2012 Jul;56(7):3928-35. doi: 10.1128/AAC.00301-12. Epub 2012 Apr 23.
Natural mutations of Plasmodium falciparum dihydrofolate reductase (PfDHFR) at A16V and S108T specifically confer resistance to cycloguanil (CYC) but not to pyrimethamine (PYR). In order to understand the nature of CYC resistance, the effects of various mutations at A16 on substrate and inhibitor bi
PMID 22526319

Cloning and heterologous expression of Plasmodium ovale dihydrofolate reductase-thymidylate synthase gene.

Tirakarn S, Riangrungroj P, Kongsaeree P, Imwong M, Yuthavong Y, Leartsakulpanich U.SourceDepartment of Chemistry, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand.
Parasitology international.Parasitol Int.2012 Jun;61(2):324-32. doi: 10.1016/j.parint.2011.12.004. Epub 2012 Jan 2.
Plasmodial bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a validated antimalarial drug target. In this study, expression of the putative dhfr-ts of Plasmodium ovale rescued the DHFR chemical knockout and a TS null bacterial strain, demonstrating its DHFR and TS catalytic fun
PMID 22234170

Japanese Journal

Influence of the Genetic Polymorphisms in the 5' Flanking and Exonic Regions of CYP2C19 on Proguanil Oxidation

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Drug Metabolism and Pharmacokinetics 24(6), 537-548, 2009
… Plasma concentrations of proguanil and cycloguanil were estimated by reverse phase HPLC after single oral doses (200 mg) of proguanil. … The mean metabolic ratios (proguanil/cycloguanil) were highest in *1/*2 or *1/*3 subjects and in *2/*2 or *2/*3 as compared to *1/*1 subjects. …
NAID 130004933464

Sensitive method for the quantitative determination of proguanil and its metabolites in rat blood and plasma by liquid chromatography-mass spectrometry

LEVEQUE Nathalie L.,CHARMAN William N.,CHIU Francis C. K.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 830(2), 314-321, 2006-01-18
NAID 10025778607

Improved method for the simultaneous determination of proguanil and its metabolites by high-performance liquid chromatography and solid-phase extraction of 100-μl capillary blood samples dried on sampling paper

BERGQVIST Y.,FUNDING L.,KANEKO A.,KRYSEN B.,LEEK T.
Journal of chromatography. B, Biomedical sciences and applications 719(1), 141-149, 1998-11-20
NAID 10024533542

Related Pictures

2D Image | Cycloguanil | C11H14ClN5 Camolar,Cycloguanil pamoate ,Cycloquanil Cycloguanil - Wikipedia, the free File:Cycloguanil.svg - Wikimedia Commons Cycloguanil pamoate,Cycloguanil embonate Cycloguanil 516-21-2 File:Cycloguanil.png - Wikimedia Commons The title molecule 1 , cycloguanil

★リンクテーブル★

リンク元	「シクログアニル」
拡張検索	「cycloguanil embonate」

「シクログアニル」

Cycloguanil
Systematic (IUPAC) name
	1-(4-chlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine
Identifiers
CAS Number	516-21-2
ATC code	P01BB02 (WHO)
PubChem	CID 9049
ChemSpider	8697
UNII	26RM326WVN
ChEMBL	CHEMBL747
Chemical data
Formula	C11H14ClN5
Molar mass	251.715 g/mol
	SMILES Clc1ccc(cc1)N2C(=N/C(=N\C2(C)C)N)\N ;
	InChI InChI=1S/C11H14ClN5/c1-11(2)16-9(13)15-10(14)17(11)8-5-3-7(12)4-6-8/h3-6H,1-2H3,(H4,13,14,15,16) ; Key:QMNFFXRFOJIOKZ-UHFFFAOYSA-N ;
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