Identification

Name
Sulfadoxine
Accession Number
DB01299
Type
Small Molecule
Groups
Approved, Investigational
Description

A long acting sulfonamide that is used, usually in combination with other drugs, for respiratory, urinary tract, and malarial infections. [PubChem]

Structure
Thumb
Synonyms
  • 4-Sulfanilamido-5,6-dimethoxypyrimidine
  • Sulfadoxina
  • Sulfadoxine
  • Sulfadoxinum
  • Sulforthomidine
  • Sulphadoxine
  • Sulphormethoxine
External IDs
J21.373J / RO-4-4393 / WR-4073
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
FansidarSulfadoxine (500 mg/1) + Pyrimethamine (25 mg/1)TabletOralGenentech, Inc.1981-10-282012-04-18Us
Fansidar TabletsSulfadoxine (500 mg) + Pyrimethamine (25 mg)TabletOralHoffmann La Roche1989-12-312000-07-27Canada
Categories
UNII
88463U4SM5
CAS number
2447-57-6
Weight
Average: 310.329
Monoisotopic: 310.073575646
Chemical Formula
C12H14N4O4S
InChI Key
PJSFRIWCGOHTNF-UHFFFAOYSA-N
InChI
InChI=1S/C12H14N4O4S/c1-19-10-11(14-7-15-12(10)20-2)16-21(17,18)9-5-3-8(13)4-6-9/h3-7H,13H2,1-2H3,(H,14,15,16)
IUPAC Name
4-amino-N-(5,6-dimethoxypyrimidin-4-yl)benzene-1-sulfonamide
SMILES
COC1=NC=NC(NS(=O)(=O)C2=CC=C(N)C=C2)=C1OC

Pharmacology

Indication

Sulfadoxine is used in combination with pyrimethamine for the treatment or prevention of malaria. It can also be used to treat various infections in livestock as well. Sulfadoxine and pyrimethamine is indicated for the treatment of Plasmodium falciparum malaria in those patients in whom chloroquine resistance is suspected.

Pharmacodynamics

Sulfadoxine helps inhibit the enzyme dihydropteroate synthetase which is an enzyme necessary in the conversion of PABA to folic acid. As folic acid is vital to the synthesis, repair, and methylation of DNA which is vital to cell growth in Plasmodium falciparum. With this vital nutrient lacking, the parasite has difficulty in reproducing.

Mechanism of action

Sulfadoxine is a sulfa drug, often used in combination with pyrimethamine to treat malaria. This medicine may also be used to prevent malaria in people who are living in, or will be traveling to, an area where there is a chance of getting malaria. Sulfadoxine targets Plasmodium dihydropteroate synthase and dihydrofolate reductase. Sulfa drugs or Sulfonamides are antimetabolites. They compete with para-aminobenzoic acid (PABA) for incorporation into folic acid. The action of sulfonamides exploits the difference between mammal cells and other kinds of cells in their folic acid metabolism. All cells require folic acid for growth. Folic acid (as a vitamin) diffuses or is transported into human cells. However, folic acid cannot cross bacterial (and certain protozoan) cell walls by diffusion or active transport. For this reason bacteria must synthesize folic acid from p-aminobenzoic acid.

TargetActionsOrganism
ADihydropteroate synthetaseNot AvailablePlasmodium falciparum
UBifunctional dihydrofolate reductase-thymidylate synthase
inhibitor
Plasmodium falciparum (isolate K1 / Thailand)
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be increased when used in combination with Sulfadoxine.
AcarboseThe therapeutic efficacy of Acarbose can be increased when used in combination with Sulfadoxine.
AcepromazineThe risk or severity of QTc prolongation can be increased when Sulfadoxine is combined with Acepromazine.
AceprometazineThe risk or severity of QTc prolongation can be increased when Sulfadoxine is combined with Aceprometazine.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be increased when used in combination with Sulfadoxine.
AcetophenazineThe risk or severity of QTc prolongation can be increased when Sulfadoxine is combined with Acetophenazine.
AICA ribonucleotideThe therapeutic efficacy of AICA ribonucleotide can be increased when used in combination with Sulfadoxine.
AlbiglutideThe therapeutic efficacy of Albiglutide can be increased when used in combination with Sulfadoxine.
AlimemazineThe risk or severity of QTc prolongation can be increased when Sulfadoxine is combined with Alimemazine.
AlogliptinThe therapeutic efficacy of Alogliptin can be increased when used in combination with Sulfadoxine.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015413
KEGG Drug
D00580
KEGG Compound
C07630
PubChem Compound
17134
PubChem Substance
46507915
ChemSpider
16218
ChEBI
9329
ChEMBL
CHEMBL1539
Therapeutic Targets Database
DAP000638
PharmGKB
PA451540
Wikipedia
Sulfadoxine
ATC Codes
G01AE10 — Combinations of sulfonamides

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAutoimmune Diseases / Lymphoproliferative Disorders1
2, 3CompletedPreventionPlasmodium Infections1
2, 3CompletedTreatmentPlasmodium Infections1
3Active Not RecruitingPreventionPlasmodium Infections / Pregnancy1
3CompletedPreventionPlasmodium Infections1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Pneumonia, Pneumocystis Carinii1
3CompletedTreatmentPlasmodium Infections1
3TerminatedTreatmentPlasmodium Infections1
3WithdrawnTreatmentPlasmodium Falciparum Malaria1
4CompletedPreventionPlasmodium Infections1
4CompletedTreatmentPlasmodium Falciparum Malaria / Plasmodium Infections1
4RecruitingPreventionMalaria caused by Plasmodium falciparum1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • F Hoffmann La Roche Ltd.
  • F Hoffmann-La Roche Ltd.
Dosage forms
FormRouteStrength
TabletOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)190-194 °CPhysProp
logP0.70SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.296 mg/mLALOGPS
logP0.72ALOGPS
logP0.58ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)6.12ChemAxon
pKa (Strongest Basic)2.55ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area116.43 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity77.81 m3·mol-1ChemAxon
Polarizability30.01 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9602
Blood Brain Barrier-0.5345
Caco-2 permeable-0.59
P-glycoprotein substrateNon-substrate0.8126
P-glycoprotein inhibitor INon-inhibitor0.832
P-glycoprotein inhibitor IINon-inhibitor0.8892
Renal organic cation transporterNon-inhibitor0.9164
CYP450 2C9 substrateNon-substrate0.693
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateNon-substrate0.6464
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8703
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6052
Ames testNon AMES toxic0.6456
CarcinogenicityNon-carcinogens0.8265
BiodegradationNot ready biodegradable0.996
Rat acute toxicity1.8756 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9907
hERG inhibition (predictor II)Non-inhibitor0.7221
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-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0a4i-2901000000-8862dd6e93b57f07349b
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0a4i-3910000000-fbde0b31ef009afef44d

Taxonomy

Description
This compound belongs to the class of organic compounds known as aminobenzenesulfonamides. These are organic compounds containing a benzenesulfonamide moiety with an amine group attached to the benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzenesulfonamides
Direct Parent
Aminobenzenesulfonamides
Alternative Parents
Benzenesulfonyl compounds / Aniline and substituted anilines / Alkyl aryl ethers / Pyrimidines and pyrimidine derivatives / Organosulfonamides / Imidolactams / Heteroaromatic compounds / Aminosulfonyl compounds / Azacyclic compounds / Primary amines
show 3 more
Substituents
Aminobenzenesulfonamide / Benzenesulfonyl group / Aniline or substituted anilines / Alkyl aryl ether / Pyrimidine / Organosulfonic acid amide / Imidolactam / Organic sulfonic acid or derivatives / Organosulfonic acid or derivatives / Sulfonyl
show 16 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
sulfonamide, pyrimidines (CHEBI:9329)

Targets

Kind
Protein
Organism
Plasmodium falciparum
Pharmacological action
Yes
General Function
Dihydropteroate synthase activity
Specific Function
Not Available
Gene Name
Not Available
Uniprot ID
Q27738
Uniprot Name
Dihydropteroate synthetase
Molecular Weight
43370.845 Da
References
  1. Raman J, Little F, Roper C, Kleinschmidt I, Cassam Y, Maharaj R, Barnes KI: Five years of large-scale dhfr and dhps mutation surveillance following the phased implementation of artesunate plus sulfadoxine-pyrimethamine in Maputo Province, Southern Mozambique. Am J Trop Med Hyg. 2010 May;82(5):788-94. doi: 10.4269/ajtmh.2010.09-0401. [PubMed:20439956]
  2. Zhang GQ, Guan YY, Zheng B, Wu S, Tang LH: Molecular assessment of Plasmodium falciparum resistance to antimalarial drugs in China. Trop Med Int Health. 2009 Oct;14(10):1266-71. doi: 10.1111/j.1365-3156.2009.02342.x. [PubMed:19772548]
  3. Lumb V, Das MK, Mittra P, Ahmed A, Kumar M, Kaur P, Dash AP, Singh SS, Sharma YD: Emergence of an unusual sulfadoxine-pyrimethamine resistance pattern and a novel K540N mutation in dihydropteroate synthetase in Plasmodium falciparum isolates obtained from Car Nicobar Island, India, after the 2004 Tsunami. J Infect Dis. 2009 Apr 1;199(7):1064-73. doi: 10.1086/597206. [PubMed:19220141]
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. Eriksen J, Mwankusye S, Mduma S, Kitua A, Swedberg G, Tomson G, Gustafsson LL, Warsame M: Patterns of resistance and DHFR/DHPS genotypes of Plasmodium falciparum in rural Tanzania prior to the adoption of sulfadoxine-pyrimethamine as first-line treatment. Trans R Soc Trop Med Hyg. 2004 Jun;98(6):347-53. [PubMed:15099990]
  2. Happi CT, Gbotosho GO, Folarin OA, Akinboye DO, Yusuf BO, Ebong OO, Sowunmi A, Kyle DE, Milhous W, Wirth DF, Oduola AM: Polymorphisms in Plasmodium falciparum dhfr and dhps genes and age related in vivo sulfadoxine-pyrimethamine resistance in malaria-infected patients from Nigeria. Acta Trop. 2005 Sep;95(3):183-93. [PubMed:16023986]
  3. Fernandes NE, Cravo P, do Rosario VE: [Sulfadoxine-pyrimethamine resistance in Maputo, Mozambique: presence of mutations in the dhfr and dhps genes of Plasmodium falciparum]. Rev Soc Bras Med Trop. 2007 Jul-Aug;40(4):447-50. [PubMed:17876469]

Drug created on June 30, 2007 08:21 / Updated on November 02, 2018 04:59