Tiabendazole (INN, BAN), also known as thiabendazole (AAN, USAN) or TBZ and the trade names Mintezol, Tresaderm, and Arbotect, is a preservative,[1] an antifungal agent, and an antiparasitic agent.
Tiabendazole is also used as a food additive,[2][3] a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU,[4] Australia and New Zealand.[5]
As an antiparasitic, tiabendazole is able to control roundworms (such as those causing strongyloidiasis),[7]hookworms, and other helminth species which infect wild animals, livestock, and humans.[8] First approved for use in sheep in 1961 and horses in 1962, resistance to this drug was first found in Haemonchus contortus in 1964, and then in the two other major small ruminant nematode parasites, Teladorsagia circumcincta and Trichostrongylus colubriformis.[9]
Fungicide
Tiabendazole acts as a fungicide through binding fungal tubulin. Resistant Aspergillus nidulans specimens were found to have a mutation in the gene coding for β-tubulin, which was reversible by a mutation in the gene for α-tubulin. This showed that thiabendazole binds to both α- and β-tubulin.[10]
Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells.[12]
Pharmacodynamics
Tiabendazole works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.[13]
Safety
The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below LD50 level).[citation needed] Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur.[citation needed] Carcinogenic effects have been shown at higher doses.[14]
Synthesis
Intermediate aryl amidine (2) is prepared by aluminium trichloride-catalyzed addition of aniline to the nitrile of 4-cyanothiazole (1).[15][16] The amidine (2) is then converted to its N-chloro derivative 3 with sodium hypochlorite (NaOCl). Upon treatment with base, this undergoes a nitrene insertion reaction (4) to produce tiabendazole (5).
Tiabendazole synthesis
An alternative synthesis involves reacting 4-thiazolecarboxamide with o-phenylenediamine in polyphosphoric acid.[17]
^Gilman AG, Rall TW, Nies AS, Taylor P, eds. (1990). Goodman and Gilman's The Pharmacological Basis of Therapeutics (8th ed.). New York, NY: Pergamon Press. p. 970.
^Grenda VJ, Jones RE, Gal G, Sletzinger M (1965). "Novel Preparation of Benzimidazoles from N-Arylamidines. New Synthesis of Thiabendazole". The Journal of Organic Chemistry. 30: 259–261. doi:10.1021/jo01012a061.
^US 3336192, Sarett LH, Brown HD, "Anthelmintic substituted benzimidazole compositions", issued 1967, assigned to Merck & Co.
^Brown HD, Matzuk AR, Ilves I, Peterson LH, Harris SA, Sarett LH, et al. (1961). "Antiparasitic Drugs. IV. 2-(4'-Thiazolyl)-Benzimidazole, A New Anthelmintic". Journal of the American Chemical Society. 83 (7): 1764–1765. doi:10.1021/ja01468a052.
^ZA 6800351, Hoff DR, Fisher MH, "Anthelmintic 5-substituted aminobenzimidazoles", issued 1969, assigned to Merck and Co., Inc. Chemical Abstracts 72, 90461 (1970).
^Hoff DR, Fisher MH, Bochis RJ, Lusi A, Waksmunski F, Egerton JR, et al. (May 1970). "A new broad-spectrum anthelmintic: 2-(4-thiazolyl)-5-isopropoxycarbonylamino-benzimidazole". Experientia. 26 (5): 550–551. doi:10.1007/BF01898506. PMID4245814. S2CID26567527.
