Proguanil

Identification

Summary

Proguanil is a medication indicated for prophylaxis and treatment of Plasmodium falciparum malaria.

Brand Names
Malarone
Generic Name
Proguanil
DrugBank Accession Number
DB01131
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 253.731
Monoisotopic: 253.109423244
Chemical Formula
C11H16ClN5
Synonyms
  • 1-(p-Chlorophenyl)-5-isopropylbiguanide
  • Chlorguanide
  • Chloroguanide
  • Proguanil
  • Proguanile
  • Proguanilo
  • Proguanilum

Pharmacology

Indication

For 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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination for prophylaxis ofMalaria caused by plasmodium falciparumCombination Product in combination with: Atovaquone (DB01117)••••••••••••
Used in combination to treatAcute, uncomplicated malaria caused by plasmodium falciparumCombination Product in combination with: Atovaquone (DB01117)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Proguanil 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 action

Proguanil 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.

TargetActionsOrganism
ADihydrofolate reductase
inhibitor
Humans
UBifunctional dihydrofolate reductase-thymidylate synthase
inhibitor
Plasmodium falciparum (isolate K1 / Thailand)
Absorption

Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg.

Volume of distribution

Not Available

Protein binding

Approximately 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.

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Route of elimination

Not Available

Half-life

Approximately 20 hours

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2C19CYP2C19*2(A;A)A Allele, homozygoteEffect Directly StudiedPatients with this genotype have reduced metabolism of proguanil.Details
Cytochrome P450 2C19CYP2C19*3(A;A)A Allele, homozygoteEffect Directly StudiedPatients with this genotype have reduced metabolism of proguanil.Details
Cytochrome P450 2C19CYP2C19*2ANot Available681G>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*2BNot Available681G>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*4Not Available1A>GEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*5Not Available1297C>TEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*6Not Available395G>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*7Not Available19294T>AEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*22Not Available557G>C / 991A>GEffect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*24Not Available99C>T / 991A>G  … show all Effect InferredPoor metabolizer, lower dose requirementDetails
Cytochrome P450 2C19CYP2C19*35Not Available12662A>GEffect InferredPoor metabolizer, lower dose requirementDetails

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe metabolism of Proguanil can be increased when combined with Abatacept.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Proguanil.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Proguanil.
AcenocoumarolProguanil may increase the anticoagulant activities of Acenocoumarol.
AcetaminophenThe metabolism of Acetaminophen can be decreased when combined with Proguanil.
Food Interactions
  • Take with food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Proguanil hydrochlorideR71Y86M0WT637-32-1SARMGXPVOFNNNG-UHFFFAOYSA-N
Product Images
International/Other Brands
Paludrine
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Paludrine Tab 0.1gmTablet100 mg / tabOralAyerst Laboratories1974-12-311997-08-15Canada flag
Paludrine Tab 100mgTablet100 mgOralWyeth Ayerst Canada Inc.1996-10-252005-02-28Canada flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Atovaquon/Proguanil-Hydrochlorid Glenmark 250 mg /100 mg FilmtablettenProguanil hydrochloride (100 mg) + Atovaquone (250 mg)Tablet, film coatedOralGlenmark Arzneimittel Gmb H2017-06-19Not applicableAustria flag
Atovaquon/Proguanilhydrochlorid STADA 250 mg/100 mg FilmtablettenProguanil hydrochloride (100 mg) + Atovaquone (250 mg)Tablet, film coatedOralStada Arzneimittel Gmb H2012-08-22Not applicableAustria flag
Atovaquone and Proguanil HClProguanil hydrochloride (100 mg/1) + Atovaquone (250 mg/1)Tablet, film coatedOralPrasco Laboratories2012-07-27Not applicableUS flag
Atovaquone and Proguanil HClProguanil hydrochloride (100 mg/1) + Atovaquone (250 mg/1)Tablet, film coatedOralPD-Rx Pharmaceuticals, Inc.2012-07-27Not applicableUS flag
Atovaquone and Proguanil HClProguanil hydrochloride (100 mg/1) + Atovaquone (250 mg/1)Tablet, film coatedOralbryant ranch prepack2012-07-27Not applicableUS flag

Categories

ATC Codes
P01BB01 — ProguanilP01BB51 — Proguanil and atovaquoneP01BB52 — Chloroquine and proguanil
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 1-arylbiguanides. These are organonitrogen compounds containing a biguanide that is N-arylsubstituted at only the 1-position.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Guanidines
Direct Parent
1-arylbiguanides
Alternative Parents
Chlorobenzenes / Aryl chlorides / Carboximidamides / Organopnictogen compounds / Organochlorides / Imines / Hydrocarbon derivatives
Substituents
1-arylbiguanide / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Benzenoid / Carboximidamide / Chlorobenzene / Halobenzene / Hydrocarbon derivative / Imine
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
monochlorobenzenes, biguanides (CHEBI:8455)
Affected organisms
  • Plasmodium

Chemical Identifiers

UNII
S61K3P7B2V
CAS number
500-92-5
InChI Key
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
1-[N'-(4-chlorophenyl)carbamimidamido]-N-(propan-2-yl)methanimidamide
SMILES
CC(C)NC(=N)NC(=N)NC1=CC=C(Cl)C=C1

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 References
Not Available
Human Metabolome Database
HMDB0015263
KEGG Compound
C07631
PubChem Compound
4923
PubChem Substance
46506228
ChemSpider
4754
BindingDB
50227829
RxNav
2382
ChEBI
8455
ChEMBL
CHEMBL1377
ZINC
ZINC000095452610
Therapeutic Targets Database
DAP000634
PharmGKB
PA451124
PDBe Ligand
XEW
Drugs.com
Drugs.com Drug Page
Wikipedia
Proguanil
PDB Entries
8f4t

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentMalaria1
4CompletedNot AvailableMalaria1
4CompletedBasic ScienceRabies1
4CompletedPreventionHuman Immunodeficiency Virus (HIV) Infections / Malaria1
4CompletedPreventionMalaria caused by Plasmodium falciparum1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • A-S Medication Solutions LLC
  • GlaxoSmithKline Inc.
  • St Mary's Medical Park Pharmacy
Dosage Forms
FormRouteStrength
TabletOral
Tablet, film coatedOral
Tablet, film coatedOral100 MG
TabletOral
TabletOral100 mg / tab
TabletOral100 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)129 °CPhysProp
water solubility156 mg/LNot Available
logP2.53SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.116 mg/mLALOGPS
logP2.29ALOGPS
logP2.38Chemaxon
logS-3.3ALOGPS
pKa (Strongest Basic)10.4Chemaxon
Physiological Charge2Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count5Chemaxon
Polar Surface Area83.79 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity91.65 m3·mol-1Chemaxon
Polarizability26.75 Å3Chemaxon
Number of Rings1Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0006-9820000000-cb5312c89efbffe9e258
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f7o-6920000000-9cc914f9810e8ef6a3c0
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-1190000000-e66f070862f9d55cf79d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0w2c-7920000000-eb0784ba4dcec84acd4d
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gbc-9200000000-c9d6c640944dc3839be1
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-9300000000-fd5c650b6b690e1e129d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0ikc-9300000000-82c14e50aa1e436a8c1d
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-143.2485782
predicted
DarkChem Lite v0.1.0
[M-H]-169.26653
predicted
DeepCCS 1.0 (2019)
[M+H]+144.8346782
predicted
DarkChem Lite v0.1.0
[M+H]+171.62453
predicted
DeepCCS 1.0 (2019)
[M+Na]+143.5847782
predicted
DarkChem Lite v0.1.0
[M+Na]+177.71767
predicted
DeepCCS 1.0 (2019)

Targets

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Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
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Kind
Protein
Organism
Humans
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 pre...
Gene Name
DHFR
Uniprot ID
P00374
Uniprot Name
Dihydrofolate reductase
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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 f...
Gene Name
Not Available
Uniprot ID
P13922
Uniprot Name
Bifunctional dihydrofolate reductase-thymidylate synthase
Molecular Weight
71816.775 Da
References
  1. Basco LK, Eldin de Pecoulas P, Wilson CM, Le Bras J, Mazabraud A: Point mutations in the dihydrofolate reductase-thymidylate synthase gene and pyrimethamine and cycloguanil resistance in Plasmodium falciparum. Mol Biochem Parasitol. 1995 Jan;69(1):135-8. doi: 10.1016/0166-6851(94)00207-4. [Article]

Enzymes

Kind
Protein
Organism
Humans
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 un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [Article]
Kind
Protein
Organism
Humans
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
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. [Article]
  2. Hoskins JM, Shenfield GM, Gross AS: Relationship between proguanil metabolic ratio and CYP2C19 genotype in a Caucasian population. Br J Clin Pharmacol. 1998 Nov;46(5):499-504. doi: 10.1046/j.1365-2125.1998.00807.x. [Article]
  3. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Bapiro TE, Egnell AC, Hasler JA, Masimirembwa CM: Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48