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| | Thiabendazole Chemical Properties |
| Melting point | 298-301°C | | Boiling point | 446.0±37.0 °C(Predicted) | | density | 1.2271 (rough estimate) | | vapor pressure | Negligible at room temperature | | refractive index | 1.5500 (estimate) | | storage temp. | Sealed in dry,Room Temperature | | solubility | Soluble in methanol and dimethyl sulfoxide. | | pka | pKa 4.7 (Uncertain) | | form | powder | | color | light yellow | | Water Solubility | 0.005 g/100 mL | | Merck | 14,9289 | | BRN | 611403 | | InChIKey | WJCNZQLZVWNLKY-UHFFFAOYSA-N | | LogP | 2.470 | | CAS DataBase Reference | 148-79-8(CAS DataBase Reference) | | NIST Chemistry Reference | Thiabendazole(148-79-8) | | EPA Substance Registry System | Thiabendazole (148-79-8) |
| | Thiabendazole Usage And Synthesis |
| Physical properties | MW 201, pKa not known. Practically insoluble in water.
| | Pharmacology and mechanism of action | Thiabendazole is a benzimidazole derivative introduced as a veterinary drug during the 1960s and later as a human anthelminthic drug. It has a broad spectrum anthelminthic activity being effective against various types of nematode infections. It is both ovicidal and larvicidal. It is also highly effective against many saprophytic and pathogenic fungi in vitro and has also shown anti-inflammatory, antipyretic and analgesic properties in laboratory animals[1]. Clinically, it is primarily used against Strongyloides stercoralis and cutaneous larva migrans.
The mechanism of action is not clearly understood. It has been shown to inhibit the mitochondrial fumurate reductase, which is specific for helminths[2]. Thiabendazole may also affect parasite microtubules, by a mechanism similar to that described for mebendazole (see Mebendazole).
| | Indications | Thiabendazole is primarily indicated in infections with Strongyloides stercoralis and cutaneous larva migrans. It may also prove useful against Capillaria philippinensis, Trichostrongylus species and alleviate symptoms during the invasion stage of trichinosis.
| | Interactions | In a single patient, thiabendazole has been reported to have increased the plasma half-life of theophylline by three-fold because of decreased plasma clearance[3].
| | Side effects | Common side effects include nausea, vomiting, headache, dizziness, and abdominal pain. In one clinical study around 40% of the patients treated experienced side effects including vomiting (25%), headache (11%) and dizziness (11%) [4]. In another study [5], 43 patients treated with the recommended doses of the drug, 34 (89%) suffered side effects. Majorcomplaints included nausea (67%), smelly urine (26%), neuropsychiatric symptoms (23%), malaise (16%), dizziness (16%), anorexia (7%), vomiting (7%), abdominal pain (7%), ‘thought going to die’ (7%), and headache (5%). The patients in the study were largely elderly. Side effects occurred 1–4 hours after drug ingestion and lasted for up to 8–12 hours.
Occasionally cholestatic jaundice, skin reactions, crystalluria, diarrhoea, headache, fatigue, drowsiness and drying of mucous membranes may occur. Hyperglycaemia, disturbances in colour vision, bradycardia and hypotension are uncommon. Hypersensitivity reactions such as fever, oedema, and lymphoadenopathy are also rare [4,6]. Single cases of StevensJohnsons syndrome and toxic epidermal necrosis have been reported [6]. The urine of some patients may have an odour much like that observed after eating asparagus; it is attributed to the presence of a metabolite [1,7].
| | Contraindications and precautions | Thiabendazole should be given with caution to patients with a history of drug hypersensitivity. Dosage reductions must be made in patients with kidney or hepatic failure. Thiabendazole is a potent inhibitor of cytochrome P450, and it is likely to increase the plasma concentrations of drugs metabolized by this route.
| | Preparations | • Mintesol® (Merck Sharp & Dohme). Oral suspension 100 mg/ml. Tablets 500 mg.
| | Description | Thiabendazole is a kind of fungicide and parasiticide. As a fungicide, it can be used for the treatment of mold, blight and many other fungal diseases occurring in fruits and vegetable. As an antiparasitic, it is capable of treating roundworms, hookworms, and other kinds of helminth species that can attack wild animals, livestock and humans. It also has effects of inhibiting the angiogenesis of cells. The mechanism of action is still not fully understood. It has found that Thiabendazole is capable of suppressing the helminth-specific mitochondrial enzyme fumarate reductase, further inhibiting the citric acid cycle, mitochondrial respiration and ATP production, leading to helminth’s death. It may also inhibit the microtubule polymerization processes.
| | References | 1. Robinson HJ, Phases HF, Graessle DE (1969). Thiabendazole: lexicological, pharmacological and antifungal properties. Texas Rep Biol Med, 27, 537–560.
2. Sheth UK (1975). Thiabendazole inhibited the fumarate reductase metabolism of helminths. Prog Drug Res, 19, 147.
3. Schneider D, GannonR, Sweeney K, Shore E (1990). Theophylline and antiparasitic drug interactions. A case report and study of the influence of thiabendazole and mebendazole on theophylline pharmacokinetics in adults. Chest, 97, 84–87.
4. Farahmandian I, Arfaa F, Jalali H, Reza M (1977). Comparative studies on the evaluation of the effect of new anthelminthics on various intestinal helminthiasis in Iran. Chemotherapy, 23, 98.
5. Grove DI (1982). Treatment of strongyloidiasis with thiabendazole: an analysis of toxicity and effectiveness. Trans R Soc Trop Med Hyg, 76, 114–118.
6. Robinson HM, Samorodin CS (1976). Thiabendazole-induced toxic epidermal necrolysis. Arch Dermatol, 112, 1757–1760.
7. Robinson HJ, Phases HF, Graessle DE (1978). The lexicological and antifungal properties of thiabendazole. Ecotoxicol Environ Safety, 1, 471–476.
| | Description | Thiabendazole is a broad-spectrum anthelmintic that is active against a variety of helminths. In sheep, thiabendazole (50 mg/kg) kills greater than 95% of adult worms from ten genera, including Trichostrongylus, Cooperia, Nematodirus, Ostertagia, Haemonchus, Oesophagostomum, Bunostomum, Strongyloides, Chabertia, and Trichuris. It also inhibits production of eggs and disrupts larval development. Thiabendazole inhibits fumarate reductase in helminths, which inhibits succinate formation, and therefore energy production through the citric acid cycle. It also inhibits methionine aminopeptidase in E. coli (Ki = 40 nM; IC50 = 47.2 nM). Formulations containing thiabendazole have been used in the control of parasitic infections in livestock. | | Description | Thiabendazole is
also a broad-spectrum systemic fungicide against many
fungal pathogens, although this compound was originally
introduced as an anthelminthic (25). | | Chemical Properties | Light yellow powder | | Originator | Mintezol,MSD,US,1967 | | Uses | A drug used in the treatment of helminthiases | | Uses | anticoagulant, rodenticide | | Uses | Thiabendazole is widely used as a post-harvest systemic fungicide
on citrus and bananas. It is active against fruit rots in bananas, citrus,
apples and pears; bulb and corm rots in ornamentals; storage rots in sweet
potato and potato and is also used to control Dutch elm disease. It is the
original benzimidazole anthelmintic for both human and animal health
usages. | | Uses | Systemic fungicide used for diseases of fruits and vegetables and for control of
Dutch elm disease. | | Definition | ChEBI: A member of the class of benzimidazoles carrying a 1,3-thiazol-4-yl substituent at position 2. A mainly post-harvest fungicide used to control a wide range of diseases including Aspergillus, Botrytis, Cladosporium and Fusarium. | | Manufacturing Process | 6.5 grams of thiazole-4-carboxylic acid is stirred with 5.9 grams of thionyl
chloride in 20 ml xylene for 10 hours at room temperature to form 4-thiazolyl
acid chloride. 1.3 grams of 4-thiazolyl acid chloride and 1.3 grams of onitroaniline
are then stirred together in 3.5 ml of pyridine at room
temperature for about 12 hours. At the end of this time, the mixture is
quenched in ice water and the solid nitroanilide recovered by filtration and
washed with dilute sodium carbonate solution. The solid is suspended in 15 ml
of glacial acetic acid, and 8 ml of 6 N hydrochloric acid added to the
suspension. 6 grams of zinc dust is added in small portions to the acetic
mixture. After the zinc addition is complete, and the reaction is essentially
finished (by visual observation), the reaction mixture is filtered and the filtrate
neutralized with concentrated ammonium hydroxide to precipitate 2-(4'-
thiazolyl)-benzimidazole. The product is purified by recrystallization from ethyl
acetate, according to US Patent 3,274,207. | | Therapeutic Function | Anthelmintic | | Synthesis Reference(s) | The Journal of Organic Chemistry, 30, p. 259, 1965 DOI: 10.1021/jo01012a061 | | General Description | White or cream-colored odorless, tasteless powder. Sublimes above 590°F. Fluoresces in acidic solution. Formulated as a dust, flowable powder or wettable powder for use as a systemic fungicide and anthelmintic. | | Air & Water Reactions | Insoluble in water. | | Reactivity Profile | Thiabendazole is incompatible with a number of pesticides, including copper-containing fungicides, and with highly alkaline materials. Thiabendazole is a chelating agent, binding many metals including iron, but not calcium | | Fire Hazard | Flash point data for Thiabendazole are not available; however, Thiabendazole is probably combustible. | | Agricultural Uses | Fungicide: Thiabendazole is a fungicide used to control blight,
mold, stain and rot that are found on fruit and vegetables;
Dutch elm disease; and diseases found in food storage
and other diseases. It is also used to treat roundworms and
similar conditions in livestock and humans. Registered
for use in EU countries. A U.S. EPA restricted use
Pesticide (RUP).
U.S. Maximum Allowable Residue Levels for Thiabendazole
and its metabolite benzimidazole (free and conjugated) in
or on the following food commodities:[40CFR 180.242(a)
(1)]: apple, wet pomace 12.0 ppm; Avocado (There are no
U.S. registrations on the indicated commodity) 10.0 ppm;
banana, post harvest 3.0 ppm; bean, dry, seed 0.1 ppm;
beet, sugar, dried pulp 3.5 ppm; beet, sugar, roots 0.25 ppm;
beet, sugar, tops 10.0 ppm; cantaloupe (There are no U.S.
registrations on the indicated commodity) 15.0 ppm; carrot,
roots, postharvest 10.0 ppm; citrus, oil 15.0 ppm; fruit,
citrus, group 10, postharvest 10.0 ppm; fruit, pome, group
11, postharvest 5.0 ppm; mango 10.0 ppm; mushroom
40.0 ppm; papaya, postharvest 5.0 ppm; potato, postharvest
10.0 ppm; soybean 0.1 ppm; strawberry (There are no U.S.
registrations on the indicated commodity) 5.0 ppm; sweet
potato (postharvest to sweet potato intended only for use as
seed) 0.05 ppm; wheat, grain 1.0 ppm; wheat, straw 1.0 ppm.
[40CFR 180.242(a)(2)]: cattle, meat 0.1 ppm; cattle, meat
byproducts 0.4 ppm; goat, meat byproducts 0.4 ppm; Hog,
meat byproducts 0.3 ppm; horse, meat byproducts 0.4 ppm;
milk 0.1 ppm; sheep, meat byproducts 0.4 ppm. [40CFR
180.2010]: Use/Limits: As a seed treatment for dry pea
(including field pea, pigeon pea, chickpea or lentil), using
a maximum application rate of 0.075 pounds of active ingredient
per 100 pounds of seed. Vines or hay grown from
treated seed may not be fed to livestock. | | Pharmaceutical Applications | Thiabendazole; a thiazolyl benzimidazole available for oral
administration. It is active against most common intestinal
nematodes. As a result of its larvicidal and ovicidal activity,
it is effective in strongyloidiasis, trichinosis, visceral larva
migrans and cutaneous larva migrans.
It is well absorbed from the small intestine. Peak plasma
levels are reached about 1–2 h after a single oral dose of the
suspension. It is extensively metabolized in the liver to the
5-hydroxy derivative, which is inactive. Most of the drug is
excreted within 24 h. About 90% is excreted in the urine,
chiefly as glucuronide or sulfate conjugates; the remainder is
passed in the feces.
A wide range of unpleasant side effects occur, including
nausea and other gastrointestinal upsets, fever and neurological
effects. It has been largely replaced by the less toxic
benzimidazole carbamates. Although active against Ascaris
lumbricoides, E. vermicularis and hookworms, it should not be
used as primary therapy for these infections. | | Trade name | AGROSOL? AGROSOL?T, (with thiram);
APL-LUSTER? ARBOTECT? BOVIZOLE?
BRODEX? CHEM-TEK? CITRUS LUSTR? DECCO
SALT NO.19? E-Z-EX? EPROFIL? EQUIVET
TZ? EQUIZOLE? FRESHGARD? FUNGICIDE
4 T? GRANOX? IRGAGUARD? LOMBRISTOP?
MERTEC? MERTECT 160? METASOL TK-100?
MINTEZOL? MINZOLUM? MK-360? MYCOZOL?
NEMAPAN? NSC 525040? OMNIZOLE?
POLIVAL? RIVAL? (captan + PCNB + thiabendazole);
RPH? RTU-VITAVAX-EXTRA? STA-FRESH? TBZ
6? TECTO? TECTO RPH? TECTO 10P? TECTO
40 F? TESTO? THIABEN? THIABENDAZOLUM?
THIABENZAZOLE? THIABENZOLE?
THIBENZOL? THIBENZOLE? THIBENZOLE 200?
THIBENZOLE ATT? TIABENDAZOLE? TOBAZ?
TOP FORM WORMER? VITAVAX?Thiabendazole
Chemical class: Benzimidazole | | Contact allergens | This fungicide and vermifuge agent is widely used in agriculture (for example, forcitrus fruits), and in medical and veterinary practice as an anthelmintic drug. | | Mechanism of action | Thiabendazole is an antihelmintic drug with a broad spectrum of action. Although the
details of its mechanism of action are not conclusively known, it seems likely that its
action is mediated by the inhibition of a specific enzyme of helminthes—fumarate reductase. Thiabendazole is active with respect to most nematode infections, including
Angyostrongylus cantonesis, Strongyloides stercoralis, Trichinella spiralis, Toxocara
canis, Toxocara cati, Ancylostoma caninum, A. braziliense, A. duodenale, Dracunculus
medinesis, Capillaria philippinesis, as well as for treating Acaris cantonesis and
Shistosoma stercoralis. Synonyms of this drug are mintezol, minzolum, and others. | | Clinical Use | 2-(4-Thiazolyl)benzimidazole (Mintezol) occurs as a whitecrystalline substance that is only slightly soluble in waterbut is soluble in strong mineral acids. Thiabendazole is abasic compound with a pKa of 4.7 that forms complexeswith metal ions.
Thiabendazole inhibits the helminth-specific enzymefumarate reductase. It is not known whether metal ionsare involved or if the inhibition of the enzyme is related tothiabendazole’s anthelmintic effect. Benzimidazole anthelminticdrugs such as thiabendazole and mebendazolealso arrest nematode cell division in metaphase by interferingwith microtubule assembly. They exhibit a highaffinity for tubulin, the precursor protein for microtubulesynthesis.
Thiabendazole has broad-spectrum anthelmintic activity.It is used to treat enterobiasis, strongyloidiasis (threadworminfection), ascariasis, uncinariasis (hookworm infection), andtrichuriasis (whipworm infection). It has also been used torelieve symptoms associated with cutaneous larva migrans(creeping eruption) and the invasive phase of trichinosis. Inaddition to its use in human medicine, thiabendazole iswidely used in veterinary practice to control intestinalhelminths in livestock. | | Safety Profile | Moderately toxic by
ingestion. An experimental teratogen. A
questionable carcinogen. Experimental
reproductive effects. Mutation data
reported. When heated to decomposition it
emits toxic fumes of SOX and NOX. See also
SULFIDES. | | Synthesis | Thiabendazole, 2-(4-thiazolyl)benzimidazole (38.1.9), is also made in
the same manner?aheterocyclization which occurs upon reacting o-phenylendiamine with
1,3-thiazol-4-carboxylic acid. 
| | Veterinary Drugs and Treatments | Thiabendazole has been used for the removal of the following parasites
in dogs: ascarids (Toxocara canis, T. leonina), Strongyloides stercoralis,
and Filaroides. It has been used systemically as an anti-fungal
agent in the treatment of nasal aspergillosis and penicillinosis.
Topical and otic use of thiabendazole for the treatment of various
fungi is also commonly employed.
Thiabendazole is indicated (labeled) for the removal of the
following parasites in cattle: Haemonchus spp., Ostertagia spp.,
Trichostrongylus spp., Nematodirus spp., Cooperia spp. and
Oesophagostomum radiatum.
Thiabendazole is indicated (labeled) for the removal of the following
parasites in sheep and goats: Haemonchus spp., Ostertagia
spp., Trichostrongylus spp., Nematodirus spp., Cooperia spp.,
Chabertia spp., Bunostomum spp. and Oesophagostomum spp.
Thiabendazole is indicated (labeled) for the removal of the
following parasites in horses: Strongylus spp., craterstomum spp.,
Oesphagodontus spp., Posteriostomum spp., Cyathostomum spp.,
Cylicocylus spp., Cylicostephanus spp., Oxyuris spp., and Parasacaris
spp.
Thiabendazole is indicated (labeled) for the removal or prevention
of the following parasites in swine: large roundworms (Ascaris
suum) (prevention), and in baby pigs infested with Strongyloides
ransomi.
Although not approved, thiabendazole has been used in pet
birds and llamas. See the Dosage section for more information.
In many geographic areas, significant thiabendazole resistance
problems have developed and, for many parasites, other anthelmintics
would be a better choice for treatment.
When used topically, thiabendazole has antidermatophytic
properties. | | Environmental Fate | Thiabendazole does not hydrolyze readily, nor it is metabolized
in soil under aerobic or anaerobic conditions. While it photodecomposes
in minutes in aqueous solutions, photodecomposition
of thiabendazole in soil did not cause more than 40%
reduction. Thiabendazole is also only slightly water soluble, and
does not migrate in soil. Thus, it is unlikely to contaminate
groundwater. If released into the atmosphere, it exists primarily
in the particulate phase. In the vapor phase, it will degrade in
the atmosphere by reacting with photochemically produced
hydroxyl radicals with an estimated half-life of 6 h. | | Metabolic pathway | The primary photolytic degradation of thiabendazole involves the
cleavage of the thiazole-benzimidazole ring linkage. In animals, thiabendazole
is extensively oxidised in bluegill sunfish, hens, goats, sheep,
cattle, mice, rats and humans, followed by conjugation. When foliarly
applied to plants, degradation to benzimidazole and its conjugates
occurred. Benzimidazole formed in plants is mainly due to photolytic
action. The primary degradation/metabolic pathways of thiabendazole in
water, soil, plants and animals are depicted in Scheme 1. | | Degradation | Thiabendazole (1) is quite stable in aqueous suspension and in acidic
media, and it is stable to heat (PM).
Opening and/or the cleavage of the thiazole-benzimidazole ring linkage
appeared to be the primary photolytic degradation pathway. Thiabendazole
was photolysed to (benzimidazol-2-yl)carboxamide (2) and
benzimidazole (3) under natural sunlight exposure on sugar beet leaf surfaces
or on glass plates (Jacob et al., 1975). Thiabendazole was also photolysed
in aqueous solution when exposed to a Pyrex glass filtered high
pressure mercury lamp (≥290 nm). In addition to 2 and 3, photoproducts
included degradates 4-8 (Murthy et al., 1996). Compound 2 was proposed
to result from hydrolysis of (benzimidazol-2-yl)nitrile (7). The rate constant
for photolysis was not affected sigruficantly by the presence of either
fulvic or humic acids, indicating that indirect photolysis does not play a
large role in the degradation of thiabendazole. |
| | Thiabendazole Preparation Products And Raw materials |
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