148-79-8 Usage
Uses
Used in Agricultural Industry:
Thiabendazole is used as a fungicide for controlling blight, mold, stain, and rot found on fruit and vegetables, Dutch elm disease, and diseases found in food storage. It is also used to treat roundworms and similar conditions in livestock and humans.
Used in Pharmaceutical Industry:
Thiabendazole is used as an anthelmintic for the treatment of helminthiases, acting against a variety of helminths and inhibiting the production of eggs and larval development. It is also used as an anticoagulant and rodenticide.
Used in Post-Harvest Protection:
Thiabendazole is widely used as a post-harvest systemic fungicide on citrus and bananas, active against fruit rots in bananas, citrus, apples, and pears; bulb and corm rots in ornamentals; and storage rots in sweet potato and potato. It is also used to control Dutch elm disease.
Used in Chemical Synthesis:
Thiabendazole is used as a chemical intermediate for the synthesis of other compounds and in the formulation of various products, such as dust, flowable powder, or wettable powder for use as a systemic fungicide and anthelmintic.
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.
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.
Originator
Mintezol,MSD,US,1967
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
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.
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—heterocyclization 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.
Check Digit Verification of cas no
The CAS Registry Mumber 148-79-8 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,4 and 8 respectively; the second part has 2 digits, 7 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 148-79:
(5*1)+(4*4)+(3*8)+(2*7)+(1*9)=68
68 % 10 = 8
So 148-79-8 is a valid CAS Registry Number.
InChI:InChI=1/C10H6N2S2/c1-2-4-9-7(3-1)12-10(14-9)8-5-13-6-11-8/h1-6H
148-79-8Relevant articles and documents
Carboxyboronate: A Versatile C1 Building Block
Holownia, Aleksandra,Tien, Chieh-Hung,Diaz, Diego B.,Larson, Reed T.,Yudin, Andrei K.
, p. 15148 - 15153 (2019)
The synthesis and applications of carboxy-MIDA-boronate, a novel C1 building block, are described. This molecule is accessible via a ruthenium tetraoxide-mediated cleavage of commercially available ethynyl-MIDA-boronate. In the course of this study, carboxy-MIDA-boronate was found to possess ambident reactivity towards nucleophiles. Carboxylic acid derivatization produces a broad range of previously unknown carbamoyl-, oxycarbo- and thiocarboboronates. Carboxy-MIDA-boronate and its derivatives undergo condensations to access borylated heterocycles with boron at positions that are difficult to access using alternate methods. The resulting heterocycles participate in the Suzuki–Miyaura cross-coupling reaction, enabling entry into diverse bis(heteroaryl) motifs. The carbon monoxide-releasing capacity of carboxy-MIDA-boronate was also examined and applied in palladium-catalyzed carbonylation.
Synthesis and biological evaluation of thiabendazole derivatives as anti-angiogenesis and vascular disrupting agents
Zhang, Chao,Zhong, Bo,Yang, Simin,Pan, Liangkun,Yu, Siwang,Li, Zhongjun,Li, Shuchun,Su, Bin,Meng, Xiangbao
, p. 3774 - 3780 (2015)
Abstract Thiabendazole, already approved by FDA for oral use as an anti-fungal and anti-helminthic drug since 1967, has recently been repurposed as a vascular disrupting agent. By optimization of the structure of the lead compound, we successfully identified compound TBZ-19 and the new derivative is over 100-fold more potent than the lead compound against the growth of four different cell lines (A549, HCT-116, HepG2 and HUVECs). The most potent two candidates TBZ-07 and TBZ-19, exhibiting moderate inhibitory cell proliferation activity, were also verified as anti-angiogenesis and vascular disrupting agents. Therefore, TBZ-07 and TBZ-19 would be promising candidates with vasculature targeting activity and merit further development.
Synthesis, characterization and biological evaluation of benzimidazole and benzindazole derivatives as anti-hypertensive agents
Silky, Sethy,Mandal, Sudip Kumar,Ewies, Ewies Fawzy,Neerupma, Dhiman,Arun, Garg
, p. 3659 - 3664 (2021/07/10)
A substituted benzimidazole and benzindazole derivatives had been synthesized having antihypertensive activity through antagonizing the angiotensin II (Ang II) receptors. The in vivo antihypertensive activity of the compounds was done with acute renal hypertension model. Two compounds TG 1 and TG 3 were found to have antihypertensive activity comparable to Telmisartan which is a prototype for Angiotensin II receptor antagonists class of drugs.In an antihypertensive study the compounds TG 1, TG 2 and TG 3 had systolic blood pressures of 147.2 mm/Hg, 168.2 mm/Hg, and 126.3 mm/Hg, respectively. This systolic blood pressure was lower than the disease control vehicle-treated rodents, which had a systolic blood pressure of 167.2 mm/Hg. The diastolic blood pressure was 119.7 mm/Hg, 124.7 mm/Hg and 88.83 mm/Hg, respectively and that of the disease control vehicle-treated rodents was 122.3 mm/Hg. TG 3 had comparable decrease in the MABP to Telmisartan. These encouraging results make compound TG 3 effective anti-hypertensive drug candidate and worthy of further investigation.
New synthesis method of thiabendazole
-
Paragraph 0026; 0035; 0036, (2020/02/20)
The invention relates to a new synthetic route of a drug commonly named as thiabendazole. Thiazole-4-formaldehyde is used as a raw material, and is condensed with hydroxylamine hydrochloride to obtainthiazole-4-formaldoxime, thiazole-4-formaldoxime is subjected to chlorination by using NCS, and then reacts with aniline to obtain N-phenylthiazole-4-methylamine oxime, then N-phenylthiazole-4-methylamine oxime reacts with p-trifluoromethyl benzoyl chloride to obtain an amidoxime ester, and finally a visible-light-catalyzed free radical reaction is adopted for cyclization to obtain thiazole. According to the method, the visible-light-catalyzed free radical reaction is used to the synthesis of thiabendazole for the first time, the reaction conditions of a high temperature and a strong acid inthe traditional synthesis method are avoided, and thereby the reaction is greener and milder. The method has a broad spectrum, and can also be used for synthesis of imidazole compounds Ia-Ial.
Preparation method of thiabendazole technical
-
Paragraph 0012; 0013; 0014; 0015, (2019/08/03)
The invention provides a preparation method of a thiabendazole technical. Compared with the prior art, in the preparation method, raw materials are equally divided into multiple parts and placed in different containers for preparation, the reaction time interval of the two adjacent reaction containers is 2-4 minutes, data in the reaction is recorded in the interval time, products obtained from thecontainers with the maximum pH value and the minimum pH value are removed, the PH value of a final product is guaranteed, and product quality is ensured.
Production raw material of thiabendazole and preparation technology of production raw material
-
Paragraph 0014-0021, (2019/08/06)
The invention provides a production raw material of thiabendazole. The production raw material mainly comprises components as follows: lactic acid, o-phenylenediamine, acetone, inorganic acid, potassium permanganate, bromine, ethyl acetate, formamide and phosphorus pentasulfide, wherein the mole ratio of lactic acid to o-phenylenediamine is 1:1.17; the ratio of ethyl acetate, formamide and phosphorus pentasulfide is 2:1:1. The raw material ratio is sophisticated, the adjusting range of PH value is narrowed in a preparation process, the conversation rate of a product is increased, and the quality of the product is improved.
AN IMPROVED PROCESS FOR THE PREPARATION OF THIABENDAZOLE
-
Page/Page column 13, (2019/02/06)
The present invention relates to an improved process for preparing thiabendazole of formula (I) with high yield, high purity, in economical and commercially viable manner for agricultural and pharmaceutical use.
Formation of Amidinyl Radicals via Visible-Light-Promoted Reduction of N-Phenyl Amidoxime Esters and Application to the Synthesis of 2-Substituted Benzimidazoles
Li, Gang,He, Ru,Liu, Qiang,Wang, Ziwen,Liu, Yuxiu,Wang, Qingmin
, p. 8646 - 8660 (2019/07/08)
We have developed a new method for the synthesis of 2-substituted benzimidazoles via amidinyl radicals generated by visible-light-promoted reduction of N-phenyl amidoxime esters in the presence of an iridium photocatalyst. This is the first report of the use of N-phenyl amidoxime esters as amidinyl radical precursors, and the first use of substituted benzene rings as amidinyl radical acceptors. This method widens the application range of substrates and overcomes the shortcomings of the traditional methods for the synthesis of 2-substituted benzimidazoles, which requires harsh reaction conditions, involves difficult-to-prepare substituted o-phenylenediamine substrates, and produces acidic waste.
Compounds and methods for treating mammalian gastrointestinal microbial infections
-
Page/Page column 6, (2018/11/30)
Described herein are compounds, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as inhibitors of IMPDH. In certain embodiments, a compound of the invention selectively inhibits a parasitic IMPDH versus a host IMPDH. Further, the invention provides pharmaceutical compositions comprising one or more compounds of the invention. The invention also relates to methods of treating various parasitic and bacterial infections in mammals. Moreover, the compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antimicrobials and immunosuppressants.
A process for the preparation method of thiabendazole
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Paragraph 0055; 0064; 0065; 0078; 0091; 0104, (2018/04/01)
The invention relates to a new method for synthesizing thiabendazole. Acetone and chlorine are taken as starting materials to synthesize chloroacetone, chloroacetone not subjected to separation can directly react with thiocarbamide to obtain 2-Amino-4-methylthiazole which is subjected to diazotization to obtain 4-methylthiazole, and 4-methylthiazole is oxidized to produce 4-thiazolecarboxylic acid, and finally, 4-thiazolecarboxylic acid reacts with o-phenylenediamine to obtain the target object thiabendazole. The thiabendazole is a broad-spectrum anthelmintic, can repel roundworms, hookworms, whipworms, pinworms, strongyloises stercoralis and trichinization, is also a broad-spectrum efficient disinfectant and is widely used as a fruit fresh-keeping agent and a bactericidal mildew inhibitor in various fields over the past decade in China.
