Benznidazole

Identification

Name
Benznidazole
Accession Number
DB11989
Type
Small Molecule
Groups
Approved
Description

Benznidazole was granted accelerated approval for the treatment of Chagas disease in children 2-12 years of age by the FDA on August 29, 2017 [9]. It is the first treatment made available in the United States for Chagas disease.

Structure
Thumb
Synonyms
Not Available
External IDs
NSC-299972 / RO 07-1051
Product Ingredients
Not Available
Approved Prescription Products
Not Available
Approved Generic Prescription Products
Not Available
Approved Over the Counter Products
Not Available
Unapproved/Other Products
Not Available
International/Other Brands
Not Available
Brand mixtures
Not Available
Categories
UNII
YC42NRJ1ZD
CAS number
22994-85-0
Weight
Average: 260.253
Monoisotopic: 260.090940262
Chemical Formula
C12H12N4O3
InChI Key
CULUWZNBISUWAS-UHFFFAOYSA-N
InChI
InChI=1S/C12H12N4O3/c17-11(14-8-10-4-2-1-3-5-10)9-15-7-6-13-12(15)16(18)19/h1-7H,8-9H2,(H,14,17)
IUPAC Name
N-benzyl-2-(2-nitro-1H-imidazol-1-yl)ethanimidic acid
SMILES
OC(CN1C=CN=C1N(=O)=O)=NCC1=CC=CC=C1

Pharmacology

Indication

For use in the treatment of Chagas disease in children 2-12 years of age [9].

Structured Indications
Not Available
Pharmacodynamics

Benznidazole is a trypanocidal agent which kills the causative organism in Chagas disease, Trypanosoma cruzi [1].

Mechanism of action

Benznidazole is thought to be reduced to various electrophilic metabolites by nitroreductases present in Trypanosoma cruzi [1]. These metabolites likely bind to proteins, lipids, DNA, and RNA resulting in damage to these macromolecules. Benznidazole has been found to increase trypanosomal death through interferon-γ which is likely present in increased amounts due to inflammation caused by macromolecule damage [3]. DNA in parasites affected by benznidazole has been found to undergo extensive unpacking with overexpression of DNA repair proteins supporting the idea of DNA damage contributing to the mechanism of the drug [2].

Absorption

Benznidazole has a bioavailability of 91.7% and a Tmax of 2.93 h [4, 5].

Volume of distribution

The apparent volume of distribution is 39.19 L [5].

Protein binding
Not Available
Metabolism

Benznidazole is metabolized by nitroreductases in Trypanosoma cruzi and by cytochrome P450 enzymes [5, 6].

Route of elimination

The metabolites of benznidazole appear to be primarily exreted in the urine [6].

Half life

The half life of elimination is 13.27 h [5].

Clearance

The apparent oral clearance is 2.04 L/h [5].

Toxicity

At clinically relevant dosages, benznidazole can produce hepatotoxicity, peripheral neuropathy, and angioedema [7, 8].

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

Interactions

Drug Interactions
DrugInteractionDrug group
BCG vaccineThe therapeutic efficacy of Bcg can be decreased when used in combination with Benznidazole.Investigational
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Benznidazole.Approved
FingolimodBenznidazole may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe risk or severity of adverse effects can be increased when Benznidazole is combined with G17DT.Investigational
GI-5005The risk or severity of adverse effects can be increased when Benznidazole is combined with GI-5005.Investigational
INGN 201The risk or severity of adverse effects can be increased when Benznidazole is combined with INGN 201.Investigational
INGN 225The risk or severity of adverse effects can be increased when Benznidazole is combined with INGN 225.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when Benznidazole is combined with Leflunomide.Approved, Investigational
NatalizumabThe risk or severity of adverse effects can be increased when Benznidazole is combined with Natalizumab.Approved, Investigational
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Benznidazole.Approved, Investigational
Rabies virus inactivated antigen, AThe risk or severity of adverse effects can be increased when Benznidazole is combined with Rabies vaccine.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Benznidazole.Approved
RindopepimutThe risk or severity of adverse effects can be increased when Benznidazole is combined with CDX-110.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Benznidazole.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Benznidazole.Approved
SRP 299The risk or severity of adverse effects can be increased when Benznidazole is combined with SRP 299.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Benznidazole.Approved, Investigational
TG4010The risk or severity of adverse effects can be increased when Benznidazole is combined with TG4010.Investigational
TofacitinibBenznidazole may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the neutropenic activities of Benznidazole.Approved, Investigational
Food Interactions
Not Available

References

Synthesis Reference
Not Available
General References
  1. Maya JD, Cassels BK, Iturriaga-Vasquez P, Ferreira J, Faundez M, Galanti N, Ferreira A, Morello A: Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comp Biochem Physiol A Mol Integr Physiol. 2007 Apr;146(4):601-20. Epub 2006 Mar 12. [PubMed:16626984 ]
  2. Rajao MA, Furtado C, Alves CL, Passos-Silva DG, de Moura MB, Schamber-Reis BL, Kunrath-Lima M, Zuma AA, Vieira-da-Rocha JP, Garcia JB, Mendes IC, Pena SD, Macedo AM, Franco GR, de Souza-Pinto NC, de Medeiros MH, Cruz AK, Motta MC, Teixeira SM, Machado CR: Unveiling benznidazole's mechanism of action through overexpression of DNA repair proteins in Trypanosoma cruzi. Environ Mol Mutagen. 2014 May;55(4):309-21. doi: 10.1002/em.21839. Epub 2013 Dec 18. [PubMed:24347026 ]
  3. Romanha AJ, Alves RO, Murta SM, Silva JS, Ropert C, Gazzinelli RT: Experimental chemotherapy against Trypanosoma cruzi infection: essential role of endogenous interferon-gamma in mediating parasitologic cure. J Infect Dis. 2002 Sep 15;186(6):823-8. Epub 2002 Aug 16. [PubMed:12198617 ]
  4. Raaflaub J, Ziegler WH: Single-dose pharmacokinetics of the trypanosomicide benznidazole in man. Arzneimittelforschung. 1979;29(10):1611-4. [PubMed:583230 ]
  5. Wiens MO, Kanters S, Mills E, Peregrina Lucano AA, Gold S, Ayers D, Ferrero L, Krolewiecki A: Systematic Review and Meta-analysis of the Pharmacokinetics of Benznidazole in the Treatment of Chagas Disease. Antimicrob Agents Chemother. 2016 Nov 21;60(12):7035-7042. Print 2016 Dec. [PubMed:27550362 ]
  6. Perin L, Moreira da Silva R, Fonseca KD, Cardoso JM, Mathias FA, Reis LE, Molina I, Correa-Oliveira R, Vieira PM, Carneiro CM: Pharmacokinetics and Tissue Distribution of Benznidazole after Oral Administration in Mice. Antimicrob Agents Chemother. 2017 Mar 24;61(4). pii: e02410-16. doi: 10.1128/AAC.02410-16. Print 2017 Apr. [PubMed:28167558 ]
  7. Miller DA, Hernandez S, Rodriguez De Armas L, Eells SJ, Traina MM, Miller LG, Meymandi SK: Tolerance of benznidazole in a United States Chagas Disease clinic. Clin Infect Dis. 2015 Apr 15;60(8):1237-40. doi: 10.1093/cid/civ005. Epub 2015 Jan 18. [PubMed:25601454 ]
  8. Davies C, Dey N, Negrette OS, Parada LA, Basombrio MA, Garg NJ: Hepatotoxicity in mice of a novel anti-parasite drug candidate hydroxymethylnitrofurazone: a comparison with Benznidazole. PLoS Negl Trop Dis. 2014 Oct 16;8(10):e3231. doi: 10.1371/journal.pntd.0003231. eCollection 2014 Oct. [PubMed:25329323 ]
  9. FDA: Benznidazole Announcement [Link]
External Links
ChemSpider
29299
BindingDB
50089916
ChEBI
133833
ChEMBL
CHEMBL110
ATC Codes
P01CA02 — Benznidazole
AHFS Codes
Not Available
PDB Entries
Not Available
FDA label
Not Available
MSDS
Download (133 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentChagas Disease2
2Unknown StatusTreatmentChronic Chagas Disease, Indeterminate1
2, 3RecruitingTreatmentChagas Disease1
3CompletedTreatmentChagas Disease1
3Unknown StatusTreatmentChagas Disease / Heart Diseases / Trypanosomiasis1
4CompletedTreatmentChagas Disease1
4Unknown StatusDiagnosticChagas Disease1
Not AvailableCompletedNot AvailableChagas Disease1
Not AvailableCompletedBasic ScienceChagas Disease1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
PropertyValueSource
melting point (°C)190-192MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.306 mg/mLALOGPS
logP1.32ALOGPS
logP1.64ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)2.28ChemAxon
pKa (Strongest Basic)4.37ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area96.23 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity68.65 m3·mol-1ChemAxon
Polarizability25.16 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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - , positiveLC-MS/MSsplash10-00kf-7921100000-e7c8d6322a8bca6ef40f
Predicted LC-MS/MS Spectrum - 10V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, PositivePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 10V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 20V, NegativePredicted LC-MS/MSNot Available
Predicted LC-MS/MS Spectrum - 40V, NegativePredicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as nitroaromatic compounds. These are c-nitro compounds where the nitro group is C-substituted with an aromatic group.
Kingdom
Organic compounds
Super Class
Organic 1,3-dipolar compounds
Class
Allyl-type 1,3-dipolar organic compounds
Sub Class
Organic nitro compounds
Direct Parent
Nitroaromatic compounds
Alternative Parents
N-substituted imidazoles / Benzene and substituted derivatives / Heteroaromatic compounds / Secondary carboxylic acid amides / Propargyl-type 1,3-dipolar organic compounds / Organic oxoazanium compounds / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic zwitterions
show 4 more
Substituents
Nitroaromatic compound / Monocyclic benzene moiety / N-substituted imidazole / Benzenoid / Azole / Imidazole / Heteroaromatic compound / Carboxamide group / Secondary carboxylic acid amide / Azacycle
show 15 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Drug created on October 20, 2016 15:08 / Updated on September 01, 2017 12:15