Identification

Name
Nifurtimox
Accession Number
DB11820
Description

Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis.11

The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result.11

Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data.10 A convenient feature of Bayer's formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.10

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 287.29
Monoisotopic: 287.057591705
Chemical Formula
C10H13N3O5S
Synonyms
  • Nifurtimox
  • Nifurtimoxum
External IDs
  • BAY 2502
  • BAY-2502
  • BAY-A2502
  • Bayer 2502
  • BAYER-2502
  • CCRIS 2201
  • DNDI1613515

Pharmacology

Indication

Nifurtimox is indicated in pediatric patients under 18 weighing at least 2.5 kg. Continued approval of this drug for this indication is dependent upon confirmatory clinical trial results.10

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Nifurtimox exerts trypanosomal activity against Trypanosoma cruzi, treating Chagas disease.6 One study reports that nifurtimox and other benzofuran derivatives reduce parasite dehydrogenase activity.4 Results of a recent phase III clinical trial13 have shown that a significant number of pediatric patients with acute or chronic Chagas disease treated with nifurtimox were immunoglobulin G (IgG) antibody negative and demonstrated at least a 20% decrease in optical density on two IgG antibody tests for T. cruzi antigens.10,14

Mechanism of action

The mechanism of action of nifurtimox has not been fully elucidated, however, is believed to occur by the activation of nitroreductase enzymes that produce reactive metabolites with a series of deleterious effects on Trypanosoma cruzi, the parasite causing Chagas disease.6,10 The antiprotozoal actions of nifurtimox occur both intracellularly and extracellularly.10 Inhibition of parasite dehydrogenase activity is another purported mode of action of nifurtimox that warrants further research.4

TargetActionsOrganism
UNitroreductases
activator
Trypanosoma cruzi
UGlyceraldehyde-3-phosphate dehydrogenase, glycosomal
inhibitor
Trypanosoma cruzi
Absorption

The average AUC of nifurtimox is estimated between 1676-2670 μg∙h/L.10 One pharmacokinetic study of healthy volunteers revealed an AUC of 5430 ng∙ml-1∙h.8 Cmax ranges between 425-568 μg/L (26–50%) after a single dose of 20 mg with food in adults. Tmax is 4 hours, ranging from 2 to 8 hours post-dose in the fed state.8,10 In a pharmacokinetic study of healthy volunteers, serum concentration was low, likely due to the first-pass effect.1

Volume of distribution

Nifurtimox crosses the blood-brain barrier and the placenta.2,10

Protein binding

The plasma protein binding of nifurtimox is approximately 42%.10 It is primarily bound to albumin.2

Metabolism

Nifurtimox is largely metabolized via nitroreductase enzymes. Two major inactive metabolites have been identified: M-4 and M-6. The M-4 metabolite is a cysteine conjugate of nifurtimox, while M-6 is likely formed by hydrolytic cleavage of the hydrazone moiety of nifurtimox. Other minor metabolites have also been identified in human plasma.9,10

Route of elimination

In the fed state, 44% of the dose was mainly recovered in the urine as metabolites. Fecal and biliary excretion of nifurtimox have not been studied.10

Half-life

The elimination half-life of nifurtimox ranges from 2.4–3.6 hours.10 A pharmacokinetic study of healthy volunteers and patients with renal failure revealed respective mean half-lives of 2.95 h and 3.95 h.8

Clearance

One pharmacokinetic study of nifurtimox revealed a clearance of 193.4 l∙h-1. In patients without renal failure; clearance was 99.7 l∙h-1.8

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

There is limited information in the literature regarding overdose with nifurtimox. Some symptoms of nifurtimox toxicity may include weight loss, anorexia, nausea, vomiting, vertigo, headache, nervous excitation, insomnia, convulsions, drowsiness, arthralgias, myalgias, disorientation, abdominal pain, mucosal edema, and skin manifestations. These symptoms are adverse effects of nifurtimox and are likely to be exaggerated with increased exposure.7

Affected organisms
  • Trypanosoma cruzi
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

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.
Not Available
Food Interactions
  • Avoid alcohol. Alcohol use during nifurtimox treatment may increase undesirable adverse effects.
  • Take with food.

Products

International/Other Brands
Lampit (Bayer)

Categories

ATC Codes
P01CC01 — Nifurtimox
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as nitrofurans. These are compounds containing a furan ring which bears a nitro group.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Furans
Sub Class
Nitrofurans
Direct Parent
Nitrofurans
Alternative Parents
Nitroaromatic compounds / Thiomorpholines / Sulfones / Heteroaromatic compounds / Propargyl-type 1,3-dipolar organic compounds / Oxacyclic compounds / Organic oxoazanium compounds / Hydrazones / Azacyclic compounds / Organopnictogen compounds
show 3 more
Substituents
1,4-thiazinane / 2-nitrofuran / Allyl-type 1,3-dipolar organic compound / Aromatic heteromonocyclic compound / Azacycle / C-nitro compound / Heteroaromatic compound / Hydrazone / Hydrocarbon derivative / Nitroaromatic compound
show 12 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
nitrofuran antibiotic (CHEBI:7566)

Chemical Identifiers

UNII
M84I3K7C2O
CAS number
23256-30-6
InChI Key
ARFHIAQFJWUCFH-IZZDOVSWSA-N
InChI
InChI=1S/C10H13N3O5S/c1-8-7-19(16,17)5-4-12(8)11-6-9-2-3-10(18-9)13(14)15/h2-3,6,8H,4-5,7H2,1H3/b11-6+
IUPAC Name
3-methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1lambda6-thiomorpholine-1,1-dione
SMILES
CC1CS(=O)(=O)CCN1\N=C\C1=CC=C(O1)[N+]([O-])=O

References

Synthesis Reference

Danong Chen, Glenn Rice. 2013. Novel formulations of nitrofurans including nifurtimox with enhanced activity with lower toxicity.US20150140089A1

General References
  1. Paulos C, Paredes J, Vasquez I, Thambo S, Arancibia A, Gonzalez-Martin G: Pharmacokinetics of a nitrofuran compound, nifurtimox, in healthy volunteers. Int J Clin Pharmacol Ther Toxicol. 1989 Sep;27(9):454-7. [PubMed:2807618]
  2. Jeganathan S, Sanderson L, Dogruel M, Rodgers J, Croft S, Thomas SA: The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers. J Pharmacol Exp Ther. 2011 Feb;336(2):506-15. doi: 10.1124/jpet.110.172981. Epub 2010 Nov 5. [PubMed:21057057]
  3. Forsyth CJ, Hernandez S, Olmedo W, Abuhamidah A, Traina MI, Sanchez DR, Soverow J, Meymandi SK: Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States. Clin Infect Dis. 2016 Oct 15;63(8):1056-1062. doi: 10.1093/cid/ciw477. Epub 2016 Jul 17. [PubMed:27432838]
  4. Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [PubMed:20178775]
  5. Cerecetto H, Gonzalez M: Antiparasitic prodrug nifurtimox: revisiting its activation mechanism. Future Microbiol. 2011 Aug;6(8):847-50. doi: 10.2217/fmb.11.74. [PubMed:21861617]
  6. Belinda S. Hall, Shane R. Wilkinson: Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation Antimicrobial agents and chemotherapy.
  7. Castro JA, Diaz de Toranzo EG: Toxic effects of nifurtimox and benznidazole, two drugs used against American trypanosomiasis (Chagas' disease). Biomed Environ Sci. 1988 Jun;1(1):19-33. [PubMed:3151755]
  8. Gonzalez-Martin G, Thambo S, Paulos C, Vasquez I, Paredes J: The pharmacokinetics of nifurtimox in chronic renal failure. Eur J Clin Pharmacol. 1992;42(6):671-3. doi: 10.1007/BF00265935. [PubMed:1623911]
  9. CA Pérez Montilla, S Moroni, N González, G Moscatelli, JM Altcheh, F García Bournissen: P38 Identification of Nifurtimox metabolites in urine of pediatric Chagas disease patients by UHPLC-MS/MS BMJ.
  10. FDA Approved Products: Lampit (nifurtimox) oral tablets [Link]
  11. CDC: Chagas disease [Link]
  12. Bioworld: Bayer’s Lampit approved by FDA for treating Chagas disease [Link]
  13. Clinicaltrials.gov: History of Changes for Study: NCT02625974 Prospective Study of a Pediatric Nifurtimox Formulation for Chagas' Disease (CHICO) [Link]
  14. Clinicaltrials.gov, Results: Prospective Study of a Pediatric Nifurtimox Formulation for Chagas' Disease (CHICO) [Link]
  15. Cayman Chem MSDS: Nifurtimox [Link]
KEGG Drug
D00833
KEGG Compound
C08002
PubChem Compound
6842999
PubChem Substance
347828167
ChemSpider
5246596
RxNav
7421
ChEBI
7566
ChEMBL
CHEMBL290960
Wikipedia
Nifurtimox

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentHuman African Trypanosomiasis (HAT)1
3Active Not RecruitingTreatmentChagas Disease1
3CompletedTreatmentTrypanosoma brucei gambiense infection1
3TerminatedTreatmentTrypanosoma brucei gambiense infection1
2Active Not RecruitingTreatmentMedulloblastomas / Neuroblastomas1
2RecruitingTreatmentChagas Disease / Trypanosoma Cruzi Infection1
2, 3CompletedTreatmentHuman African Trypanosomiasis (HAT) / Trypanosoma brucei gambiense infection1
2, 3RecruitingTreatmentChagas Disease1
2, 3TerminatedNot AvailableTrypanosoma brucei gambiense infection1
1CompletedOtherBioequivalence1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)177-183https://www.chemicalbook.com/ChemicalProductProperty_US_CB3903922.aspx
boiling point (°C)550.3±50.0 https://www.chemicalbook.com/ChemicalProductProperty_US_CB3903922.aspx
logP-0.27https://deepblue.lib.umich.edu/bitstream/handle/2027.42/146268/bcp13650.pdf?sequence=1
logS0.158https://deepblue.lib.umich.edu/bitstream/handle/2027.42/146268/bcp13650.pdf?sequence=1
pKa-1.01±0.40https://www.chemicalbook.com/ChemicalProductProperty_US_CB3903922.aspx
Predicted Properties
PropertyValueSource
Water Solubility0.285 mg/mLALOGPS
logP0.25ALOGPS
logP-0.27ChemAxon
logS-3ALOGPS
pKa (Strongest Basic)0.34ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area106.02 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity65.78 m3·mol-1ChemAxon
Polarizability26.74 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

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

Targets

1. Nitroreductases
Kind
Group
Organism
Trypanosoma cruzi
Pharmacological action
Unknown
Actions
Activator
Curator comments
Nitroreductases are a proposed target of nifurtamox, however, the mechanism of action of this drug is not fully elucidated.
This group is comprised of various nitroreductase enzymes belonging to the organism Trypanosoma cruzi (T. cruzi)
References
  1. Belinda S. Hall, Shane R. Wilkinson: Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation Antimicrobial agents and chemotherapy.
  2. Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [PubMed:20178775]
  3. FDA Approved Products: Lampit (nifurtimox) oral tablets [Link]
Kind
Protein
Organism
Trypanosoma cruzi
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
This target action is supported by limited evidence in the literature.
General Function
Nadp binding
Specific Function
Not Available
Gene Name
Not Available
Uniprot ID
P22513
Uniprot Name
Glyceraldehyde-3-phosphate dehydrogenase, glycosomal
Molecular Weight
39060.3 Da
References
  1. Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [PubMed:20178775]

Enzymes

1. Nitroreductases
Kind
Group
Organism
Trypanosoma cruzi
Pharmacological action
Unknown
Actions
Activator
Curator comments
Though the mechanism of action of this drug is not fully elucidated, activation of nitroreductase enzymes is a proposed action of nifurtimox.
This group is comprised of various nitroreductase enzymes belonging to the organism Trypanosoma cruzi (T. cruzi)
References
  1. Belinda S. Hall, Shane R. Wilkinson: Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation Antimicrobial agents and chemotherapy.
  2. Boiani M, Piacenza L, Hernandez P, Boiani L, Cerecetto H, Gonzalez M, Denicola A: Mode of action of nifurtimox and N-oxide-containing heterocycles against Trypanosoma cruzi: is oxidative stress involved? Biochem Pharmacol. 2010 Jun 15;79(12):1736-45. doi: 10.1016/j.bcp.2010.02.009. Epub 2010 Feb 21. [PubMed:20178775]
  3. FDA Approved Products: Lampit (nifurtimox) oral tablets [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Jeganathan S, Sanderson L, Dogruel M, Rodgers J, Croft S, Thomas SA: The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers. J Pharmacol Exp Ther. 2011 Feb;336(2):506-15. doi: 10.1124/jpet.110.172981. Epub 2010 Nov 5. [PubMed:21057057]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
This transporter action is supported by data from an in vitro study. Limited evidence exists in the literature for this transporter action.
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. Watson CP, Dogruel M, Mihoreanu L, Begley DJ, Weksler BB, Couraud PO, Romero IA, Thomas SA: The transport of nifurtimox, an anti-trypanosomal drug, in an in vitro model of the human blood-brain barrier: evidence for involvement of breast cancer resistance protein. Brain Res. 2012 Feb 3;1436:111-21. doi: 10.1016/j.brainres.2011.11.053. Epub 2011 Dec 4. [PubMed:22200378]

Drug created on October 20, 2016 14:50 / Updated on August 14, 2020 07:25

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