Tmic
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Record Information
Version2.0
Creation Date2009-06-17 23:53:01 UTC
Update Date2014-12-24 20:22:57 UTC
Accession NumberT3D0928
Identification
Common NameBenomyl
ClassSmall Molecule
DescriptionBenomyl (also marketed as Benlate) is a fungicide introduced in 1968 by DuPont. It is a systemic benzimidazole fungicide that is selectively toxic to microorganisms and invertebrates, especially earthworms. Benomyl binds to microtubules, interfering with cell functions, such as meiosis and intracellular transportation. The selective toxicity of benomyl as a fungicide is possibly due to its heightened effect on fungal rather than mammalian microtubules. Due to the development and worldwide prevalence of resistance of parasitic fungi to benomyl, it and similar pesticide compounds became largely ineffective.
Compound Type
  • Amine
  • Carbamate
  • Ester
  • Ether
  • Food Toxin
  • Lachrymator
  • Metabolite
  • Organic Compound
  • Pesticide
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
1-(Butylcarbamoyl)-2-benzimidazol-methylcarbamat
1-(N-Butylcarbamoyl)-2-(methoxy-carboxamido)-benzimidazol
Agrocit
Arbortrine
Arilate
BBC
Benex
Benlat
Benlate
Benlate 50
Benlate 50 W
Benlate 50W
Benomil
Benomyl 50W
Benomyl-imex
Benosan
BNM
Chinoin-fundazol
Du Pont 1991
Dupont 1991
Fibenzol
Fundasol
Fundazol
Fundazol 50WP
Fungicide 1991
Fungicide D-1991
Fungochrom
Kribenomy
Kribenomyl
MBCL
Methyl 1-(butylamino)carbonyl-1H-benzimidazol-2-ylcarbamate
Methyl 1-(butylcarbamoyl)-2-benzimidazolecarbamate
Methyl 1-(butylcarbamoyl)-2-benzimidazolylcarbamate
Methyl 1-(butylcarbamoyl)benzimidazol-2-ylcarbamate
Methyl 1-[(butylamino)carbonyl]-1H-benzimidazol-2-ylcarbamate, 9CI
Methyl N-(1-butylcarbamoyl-2-benzimidazole)carbamate
Methyl [1-(butylcarbamoyl)-1H-benzimidazol-2-yl]carbamate
NS 02 (fungicide)
Tersan 1991
Uzgen
Chemical FormulaC14H18N4O3
Average Molecular Mass290.318 g/mol
Monoisotopic Mass290.138 g/mol
CAS Registry Number17804-35-2
IUPAC NameN-butyl-2-{[hydroxy(methoxy)methylidene]amino}-1H-1,3-benzodiazole-1-carboximidic acid
Traditional Namebenomyl
SMILESCCCCN=C(O)N1C(N=C(O)OC)=NC2=CC=CC=C12
InChI IdentifierInChI=1S/C14H18N4O3/c1-3-4-9-15-13(19)18-11-8-6-5-7-10(11)16-12(18)17-14(20)21-2/h5-8H,3-4,9H2,1-2H3,(H,15,19)(H,16,17,20)
InChI KeyInChIKey=RIOXQFHNBCKOKP-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as 2-benzimidazolylcarbamic acid esters. These are aromatic heteropolycyclic compounds that contain a carbamic acid ester group, which is N-linked to the C2-atom of a benzimidazole moiety.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassBenzimidazoles
Sub Class2-benzimidazolylcarbamic acid esters
Direct Parent2-benzimidazolylcarbamic acid esters
Alternative Parents
Substituents
  • 2-benzimidazolylcarbamic acid ester
  • Imidazole-1-carbonyl group
  • N-substituted imidazole
  • Benzenoid
  • Azole
  • Imidazole
  • Carbamic acid ester
  • Heteroaromatic compound
  • Urea
  • Carbonic acid derivative
  • Azacycle
  • Organopnictogen compound
  • Carbonyl group
  • Organooxygen compound
  • Organonitrogen compound
  • Organic oxygen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point140°C
Boiling PointNot Available
Solubility0.0038 mg/mL at 20°C
LogP2.12
Predicted Properties
PropertyValueSource
Water Solubility0.24 g/LALOGPS
logP2.32ALOGPS
logP3.68ChemAxon
logS-3.1ALOGPS
pKa (Strongest Acidic)3.61ChemAxon
pKa (Strongest Basic)2.76ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area92.23 ŲChemAxon
Rotatable Bond Count5ChemAxon
Refractivity79.49 m³·mol⁻¹ChemAxon
Polarizability31.15 ųChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0006-8890000000-e030c9d552fc5c7d52daView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positivesplash10-044i-9055500000-3eca627722374bbbc14cView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0006-2790000000-f3ed3b88d515aed07a44View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-01qc-1900000000-97b4102ec19aeb0c6974View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-001i-2900000000-1aa81e2473687dd33506View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4l-2930000000-e8acc050770f45adf536View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4l-4960000000-e995e6dd540486a3ceb2View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-05ai-1900000000-c2b1949df8a55a1f654aView in MoNA
MSMass Spectrum (Electron Ionization)splash10-052f-7900000000-930ea348a291d67fe037View in MoNA
Toxicity Profile
Route of ExposureInhalation (5) ; oral (5); dermal (5)
Mechanism of ToxicityBenomyl targets beta tubulin in actively dividing cells. It binds to microtubules, interfering with cell functions, such as meiosis and intracellular transportation (2). Benomyl binds to brain tubulin with a dissociation constant of 11.9 +/- 1.2 microM. Further, benomyl binds to a novel tubulin beta binding site, distinct from the well-characterized colchicine and vinblastine binding sites. Benomyl inhibits the polymerization of brain tubulin into microtubules, with 50% inhibition occurring at a concentration of 70-75 microM (3)
MetabolismNot Available
Toxicity ValuesBenomyl is of such a low toxicity to mammals, it has been impossible to administer doses large enough to establish an LD50. It has an arbitrary LD50 of "greater than 10,000 mg/kg/day for rats".
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesIt is a systemic fungicide that is selectively toxic to microorganisms and invertebrates. It is also employed as a casting worm control agent in amenity turf situations such as golf greens and tennis courts. It is also used to control plant diseases in cereals and fruits, including citrus, bananas, strawberries, pineapples, and pomes.
Minimum Risk LevelThe Occupational Safety and Health Administration has set a permissible exposure limit of 15 mg/m3 for total exposure over an eight-hour time-weighted average.
Health EffectsSkin irritation may occur through industrial exposure, and florists, mushroom pickers and floriculturists have reported allergic reactions to benomyl. Benomyl is a potential teratogen. Studies have shown eye defects can occur at relatively high doses. A test in which rats were dosed orally demonstrated evidence of microphthalmia at dose levels of 62.5 mg/kg and above. In 1996, a Miami jury awarded US$ 4 million to a child whose mother was exposed in pregnancy to Benomyl. The child was born without eyes. The mother had been exposed to an unusually high dose of Benomyl through her occupation, during pregnancy.
SymptomsSkin redness and skin irritation. Fetuses exposed to high levels may exhibit microphthalmia (small eyes) or anaphthalmia (no eyes).
TreatmentFor acute exposures and first aid: EYES: irrigate opened eyes for several minutes under running water. INGESTION: do not induce vomiting. Rinse mouth with water (never give anything by mouth to an unconscious person). Seek immediate medical advice. SKIN: should be treated immediately by rinsing the affected parts in cold running water for at least 15 minutes, followed by thorough washing with soap and water. If necessary, the person should shower and change contaminated clothing and shoes, and then must seek medical attention. INHALATION: supply fresh air. If required provide artificial respiration.
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDNot Available
HMDB IDHMDB31767
PubChem Compound ID28780
ChEMBL IDCHEMBL327919
ChemSpider ID26771
KEGG IDC10896
UniProt IDNot Available
OMIM ID
ChEBI ID3015
BioCyc IDNot Available
CTD IDD001542
Stitch IDBenomyl
PDB IDNot Available
ACToR ID5798
Wikipedia LinkNot Available
References
Synthesis ReferenceNot Available
MSDST3D0928.pdf
General References
  1. Edlind TD, Bartlett MS, Smith JW: Characterization of the beta-tubulin gene of Pneumocystis carinii. J Protozool. 1991 Nov-Dec;38(6):62S-63S. [1818208 ]
  2. Clement MJ, Rathinasamy K, Adjadj E, Toma F, Curmi PA, Panda D: Benomyl and colchicine synergistically inhibit cell proliferation and mitosis: evidence of distinct binding sites for these agents in tubulin. Biochemistry. 2008 Dec 9;47(49):13016-25. doi: 10.1021/bi801136q. [19049291 ]
  3. Gupta K, Bishop J, Peck A, Brown J, Wilson L, Panda D. "Antimitotic antifungal compound benomyl inhibits brain microtubule polymerization and dynamics and cancer cell proliferation at mitosis, by binding to a novel site in tubulin.". Biochemistry. 2004 Jun 1;43(21):6645-55. [15157098 ]
  4. Yannai, Shmuel. (2004) Dictionary of food compounds with CD-ROM: Additives, flavors, and ingredients. Boca Raton: Chapman & Hall/CRC.
  5. IPCS Intox Database (1987). Antimony pentoxide. [Link]
  6. Fishel F (2009). Pesticide Toxicity Profile: Carbamate Pesticides. University of Florida, IFAS Extension. [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated GenesNot Available

Targets

General Function:
Identical protein binding
Specific Function:
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name:
BCHE
Uniprot ID:
P06276
Molecular Weight:
68417.575 Da
References
  1. Richard M. Krupka. 1974. On the anti-cholinesterase activity of benomyl. Pesticide Science 5(2), 211-16. DOI: 10.1002/ps.2780050212 [Link]
  2. Fishel F (2009). Pesticide Toxicity Profile: Carbamate Pesticides. University of Florida, IFAS Extension. [Link]
General Function:
Zinc ion binding
Specific Function:
Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:
ESR1
Uniprot ID:
P03372
Molecular Weight:
66215.45 Da
References
  1. Lemaire G, Mnif W, Mauvais P, Balaguer P, Rahmani R: Activation of alpha- and beta-estrogen receptors by persistent pesticides in reporter cell lines. Life Sci. 2006 Aug 15;79(12):1160-9. Epub 2006 Mar 27. [16626760 ]
General Function:
Ubiquitin protein ligase binding
Specific Function:
Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.
Gene Name:
TUBB
Uniprot ID:
P07437
Molecular Weight:
49670.515 Da
References
  1. Gupta K, Bishop J, Peck A, Brown J, Wilson L, Panda D. "Antimitotic antifungal compound benomyl inhibits brain microtubule polymerization and dynamics and cancer cell proliferation at mitosis, by binding to a novel site in tubulin.". Biochemistry. 2004 Jun 1;43(21):6645-55. [15157098 ]
General Function:
Receptor binding
Specific Function:
Chemotactic for monocytes and T-lymphocytes. Binds to CXCR3.
Gene Name:
CXCL10
Uniprot ID:
P02778
Molecular Weight:
10880.915 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC501.48 uMBSK_KF3CT_IP10_upBioSeek
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Virus receptor activity
Specific Function:
Binds LDL, the major cholesterol-carrying lipoprotein of plasma, and transports it into cells by endocytosis. In order to be internalized, the receptor-ligand complexes must first cluster into clathrin-coated pits.(Microbial infection) Acts as a receptor for hepatitis C virus in hepatocytes, but not through a direct interaction with viral proteins (PubMed:10535997, PubMed:12615904). Acts as a receptor for vesicular stomatitis virus (PubMed:23589850). In case of HIV-1 infection, may function as a receptor for extracellular Tat in neurons, mediating its internalization in uninfected cells (PubMed:11100124).
Gene Name:
LDLR
Uniprot ID:
P01130
Molecular Weight:
95375.105 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC504.44 uMBSK_SM3C_LDLR_upBioSeek
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Steroid binding
Specific Function:
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate. Is also able to catalyze the glucuronidation of 17beta-estradiol, 17alpha-ethinylestradiol, 1-hydroxypyrene, 4-methylumbelliferone, 1-naphthol, paranitrophenol, scopoletin, and umbelliferone. Isoform 2 lacks transferase activity but acts as a negative regulator of isoform 1.
Gene Name:
UGT1A1
Uniprot ID:
P22309
Molecular Weight:
59590.91 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC504.59 uMCLZD_UGT1A1_48CellzDirect
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.
Specific Function:
Gtp binding
Gene Name:
TUBA1A
Uniprot ID:
Q71U36
Molecular Weight:
50135.25 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC505.08 uMCLM_MicrotubuleCSK_72hrCellumen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Vitamin d 24-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 unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP1A1
Uniprot ID:
P04798
Molecular Weight:
58164.815 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC506.01 uMCLZD_CYP1A1_6CellzDirect
AC506.60 uMCLZD_CYP1A1_48CellzDirect
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular Weight:
56277.81 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC506.72 uMCLZD_CYP2B6_6CellzDirect
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Transcription regulatory region dna binding
Specific Function:
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.
Gene Name:
AHR
Uniprot ID:
P35869
Molecular Weight:
96146.705 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC508.91 uMTox21_AhRTox21/NCGC
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]
General Function:
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen. Participates in the bioactivation of carcinogenic aromatic and heterocyclic amines. Catalizes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin.
Gene Name:
CYP1A2
Uniprot ID:
P05177
Molecular Weight:
58293.76 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC509.39 uMCLZD_CYP1A2_24CellzDirect
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]