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Identification
NameProguanil
Accession NumberDB01131  (APRD00188)
TypeSmall Molecule
GroupsApproved
Description

Proguanil is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells. It does this by inhibiting the enzyme, dihydrofolate reductase, which is involved in the reproduction of the parasite.

Structure
Thumb
Synonyms
N-(4-Chlorophenyl)-n'-(isopropyl)-imidodicarbonimidic diamide
1-(P-Chlorophenyl)-5-isopropylbiguanide
Chlorguanide
Chloroguanide
N-(4-Chlorophenyl)-n'-(isopropyl)-imidodicarbonimidic diamide
Proguanilum
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Paludrine Tab 0.1gmtablet100 mgoralAyerst Laboratories1974-12-311997-08-15Canada
Paludrine Tab 100mgtablet100 mgoralWyeth Ayerst Canada Inc.1996-10-252005-02-28Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
ChloroguanideNot Available
PaludrineNot Available
Brand mixtures
NameLabellerIngredients
Atovaquone and Proguanil HClPd Rx Pharmaceuticals, Inc.
Atovaquone and Proguanil HydrochlorideMylan Pharmaceuticals Inc.
Atovaquone and Proguanil Hydrochloride PediatricGlenmark Pharmaceuticals Inc.,Usa
Atovaquone ProguanilSanis Health Inc
MalaroneGlaxo Smith Kline Llc
Malarone PediatricGlaxosmithkline Inc
Mylan-atovaquone/proguanilMylan Pharmaceuticals Ulc
Teva-atovaquone ProguanilTeva Canada Limited
Salts
Name/CASStructureProperties
Proguanil hydrochloride
ThumbNot applicableDBSALT001187
Categories
UNIIS61K3P7B2V
CAS number500-92-5
WeightAverage: 253.731
Monoisotopic: 253.109423244
Chemical FormulaC11H16ClN5
InChI KeyInChIKey=SSOLNOMRVKKSON-UHFFFAOYSA-N
InChI
InChI=1S/C11H16ClN5/c1-7(2)15-10(13)17-11(14)16-9-5-3-8(12)4-6-9/h3-7H,1-2H3,(H5,13,14,15,16,17)
IUPAC Name
(E)-1-({amino[(4-chlorophenyl)amino]methylidene}amino)-N'-(propan-2-yl)methenimidamide
SMILES
CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as chlorobenzenes. These are compounds containing one or more chlorine atoms attached to a benzene moiety.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassHalobenzenes
Direct ParentChlorobenzenes
Alternative Parents
Substituents
  • Chlorobenzene
  • Biguanide
  • Aryl halide
  • Aryl chloride
  • Guanidine
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboximidamide
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Imine
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the causal prevention and suppression of malaria caused by susceptible strains of P. falciparum and other species of Plasmodium found in some geographical areas of the world.
PharmacodynamicsProguanil is a biguanide derivative that is converted to an active metabolite called cycloguanil. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.
Mechanism of actionProguanil inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver.
Related Articles
AbsorptionRapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg.
Volume of distributionNot Available
Protein bindingApproximately 75%
Metabolism

Variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses.

SubstrateEnzymesProduct
Proguanil
cycloguanilDetails
Route of eliminationNot Available
Half lifeApproximately 20 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Plasmodium
PathwaysNot Available
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
rs4244285 CYP2C19*2A Allele, homozygotePoor metabolizer, lower dose requirement13680037
Cytochrome P450 2C19
Gene symbol: CYP2C19
UniProt: P33261
rs4986893 CYP2C19*3A Allele, homozygotePoor metabolizer, lower dose requirement13680037
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9544
Blood Brain Barrier+0.728
Caco-2 permeable+0.5
P-glycoprotein substrateNon-substrate0.7
P-glycoprotein inhibitor INon-inhibitor0.9482
P-glycoprotein inhibitor IINon-inhibitor0.8511
Renal organic cation transporterNon-inhibitor0.7381
CYP450 2C9 substrateNon-substrate0.7646
CYP450 2D6 substrateNon-substrate0.9115
CYP450 3A4 substrateNon-substrate0.6085
CYP450 1A2 substrateInhibitor0.8751
CYP450 2C9 inhibitorNon-inhibitor0.9591
CYP450 2D6 inhibitorInhibitor0.6507
CYP450 2C19 inhibitorNon-inhibitor0.9405
CYP450 3A4 inhibitorNon-inhibitor0.9109
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8774
Ames testNon AMES toxic0.5887
CarcinogenicityNon-carcinogens0.616
BiodegradationNot ready biodegradable0.9939
Rat acute toxicity2.6787 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9701
hERG inhibition (predictor II)Non-inhibitor0.9265
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Tabletoral
Tablet, film coatedoral
Tabletoral100 mg
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point129 °CPhysProp
water solubility156 mg/LNot Available
logP2.53SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.286 mg/mLALOGPS
logP1.9ALOGPS
logP1.89ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)19.77ChemAxon
pKa (Strongest Basic)10.12ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area88.79 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity71.07 m3·mol-1ChemAxon
Polarizability26.84 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
References
Synthesis Reference

Dhananjay Govind Sathe, Harish Kashinath Mondkar, Tanaji Shamrao Jadhav, Nitin Nivrutti Hagavane, “Process of Preparation of Proguanil.” U.S. Patent US20110263901, issued October 27, 2011.

US20110263901
General ReferencesNot Available
External Links
ATC CodesP01BB51P01BB01
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
AcepromazineThe serum concentration of Acepromazine can be increased when it is combined with Proguanil.
DapsoneThe risk or severity of adverse effects can be increased when Proguanil is combined with Dapsone.
EfavirenzThe serum concentration of Proguanil can be decreased when it is combined with Efavirenz.
RifabutinThe serum concentration of Proguanil can be decreased when it is combined with Rifabutin.
RitonavirThe serum concentration of Proguanil can be decreased when it is combined with Ritonavir.
WarfarinProguanil may increase the anticoagulant activities of Warfarin.
Food Interactions
  • Take with food.

Targets

Kind
Protein
Organism
Plasmodium falciparum (isolate K1 / Thailand)
Pharmacological action
unknown
Actions
inhibitor
General Function:
Thymidylate synthase activity
Specific Function:
Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.
Gene Name:
Not Available
Uniprot ID:
P13922
Molecular Weight:
71816.775 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Nadph binding
Specific Function:
Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.
Gene Name:
DHFR
Uniprot ID:
P00374
Molecular Weight:
21452.61 Da
References
  1. Kaneko A, Bergqvist Y, Takechi M, Kalkoa M, Kaneko O, Kobayakawa T, Ishizaki T, Bjorkman A: Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil. J Infect Dis. 1999 Apr;179(4):974-9. [PubMed:10068594 ]
  2. Vasconcelos KF, Plowe CV, Fontes CJ, Kyle D, Wirth DF, Pereira da Silva LH, Zalis MG: Mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase of isolates from the Amazon region of Brazil. Mem Inst Oswaldo Cruz. 2000 Sep-Oct;95(5):721-8. [PubMed:10998224 ]
  3. Tahar R, de Pecoulas PE, Basco LK, Chiadmi M, Mazabraud A: Kinetic properties of dihydrofolate reductase from wild-type and mutant Plasmodium vivax expressed in Escherichia coli. Mol Biochem Parasitol. 2001 Apr 6;113(2):241-9. [PubMed:11295178 ]
  4. Durand R, Jafari S, Bouchaud O, Ralaimazava P, Keundjian A, Le Bras J: Plasmodium falciparum: pfcrt and DHFR mutations are associated with failure of chloroquine plus proguanil prophylaxis in travelers. J Infect Dis. 2001 Dec 15;184(12):1633-4. [PubMed:11740746 ]
  5. Le Bras J, Durand R: The mechanisms of resistance to antimalarial drugs in Plasmodium falciparum. Fundam Clin Pharmacol. 2003 Apr;17(2):147-53. [PubMed:12667224 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine.
Gene Name:
CYP2C19
Uniprot ID:
P33261
Molecular Weight:
55930.545 Da
References
  1. Lu AH, Shu Y, Huang SL, Wang W, Ou-Yang DS, Zhou HH: In vitro proguanil activation to cycloguanil is mediated by CYP2C19 and CYP3A4 in adult Chinese liver microsomes. Acta Pharmacol Sin. 2000 Aug;21(8):747-52. [PubMed:11501186 ]
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  3. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N...
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenyto...
Gene Name:
CYP2C9
Uniprot ID:
P11712
Molecular Weight:
55627.365 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular Weight:
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23