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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
SynonymLanguageCode
N-(4-Chlorophenyl)-n'-(isopropyl)-imidodicarbonimidic diamideNot AvailableNot Available
1-(P-Chlorophenyl)-5-isopropylbiguanideNot AvailableNot Available
ChlorguanideNot AvailableNot Available
ChloroguanideNot AvailableNot Available
N-(4-Chlorophenyl)-n'-(isopropyl)-imidodicarbonimidic diamideNot AvailableNot Available
ProguanilumNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ChloroguanideNot Available
PaludrineNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number500-92-5
WeightAverage: 253.731
Monoisotopic: 253.109423244
Chemical FormulaC11H16ClN5
InChI KeySSOLNOMRVKKSON-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassHalobenzenes
Direct parentChlorobenzenes
Alternative parentsBiguanides; Aryl Chlorides; Polyamines; Amidines; Organochlorides
Substituentsaryl halide; aryl chloride; guanidine; polyamine; amidine; organohalogen; organochloride; amine; organonitrogen compound
Classification descriptionThis compound belongs to the chlorobenzenes. These are compounds containing one or more chlorine atoms attached to a benzene moiety.
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.
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
Property Value Probability
Human Intestinal Absorption + 0.9544
Blood Brain Barrier + 0.728
Caco-2 permeable + 0.5
P-glycoprotein substrate Non-substrate 0.7
P-glycoprotein inhibitor I Non-inhibitor 0.9482
P-glycoprotein inhibitor II Non-inhibitor 0.8511
Renal organic cation transporter Non-inhibitor 0.7381
CYP450 2C9 substrate Non-substrate 0.7646
CYP450 2D6 substrate Non-substrate 0.9115
CYP450 3A4 substrate Non-substrate 0.6085
CYP450 1A2 substrate Inhibitor 0.8751
CYP450 2C9 substrate Non-inhibitor 0.9591
CYP450 2D6 substrate Inhibitor 0.6507
CYP450 2C19 substrate Non-inhibitor 0.9405
CYP450 3A4 substrate Non-inhibitor 0.9109
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8774
Ames test Non AMES toxic 0.5887
Carcinogenicity Non-carcinogens 0.616
Biodegradation Not ready biodegradable 0.9939
Rat acute toxicity 2.6787 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9701
hERG inhibition (predictor II) Non-inhibitor 0.9265
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point129 °CPhysProp
water solubility156 mg/LNot Available
logP2.53SANGSTER (1994)
Predicted Properties
PropertyValueSource
water solubility2.86e-01 g/lALOGPS
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 area88.79ChemAxon
rotatable bond count2ChemAxon
refractivity71.07ChemAxon
polarizability26.84ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot 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 ReferenceNot Available
External Links
ResourceLink
KEGG CompoundC07631
PubChem Compound6178111
PubChem Substance46506228
ChemSpider4754
ChEBI8455
ChEMBLCHEMBL1377
Therapeutic Targets DatabaseDAP000634
PharmGKBPA451124
Drug Product Database2043068
Drugs.comhttp://www.drugs.com/cons/proguanil.html
WikipediaProguanil
ATC CodesP01BB01
AHFS CodesNot Available
PDB Entries
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
ArtemetherProguanil may increase the adverse effects of artemether. Combination therapy is contraindicated unless there are no other treatment options.
LumefantrineProguanil may increase the adverse effects of lumefantrine. Combination therapy is contraindicated unless there are no other treatment options.
Food Interactions
  • Take with food.

Targets

1. Dihydrofolate reductase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dihydrofolate reductase P00374 Details

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
  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
  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
  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
  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
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Bifunctional dihydrofolate reductase-thymidylate synthase

Kind: protein

Organism: Plasmodium falciparum (isolate K1 / Thailand)

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Bifunctional dihydrofolate reductase-thymidylate synthase P13922 Details

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
  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

Enzymes

1. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. 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
  3. 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. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

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. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

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. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

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. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2E1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2E1 P05181 Details

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. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13