ChemicalBook > Product Catalog > API > Synthetic Anti-infective Drugs > Antiviral drugs > Trifluridine
Basic information General Description Medical Uses Side Effects Indications and Dosage Precautions Drug Interactions Mechanism of Action Safety Related Supplier
Trifluridine Chemical Properties
- Melting point:190-193 °C (lit.)
- Density 1.4365 (estimate)
- refractive index 50 ° (C=1, H2O)
- storage temp. 2-8°C
- pkapKa 7.85 (Uncertain)
- Merck 14,9687
- CAS DataBase Reference70-00-8(CAS DataBase Reference)
Trifluridine Usage And Synthesis
- General DescriptionTrifluridine, also known as trifluorothymidine, F3TdR,F3T is a fluorinated pyrimidine nucleoside that has in vitro inhibitory activity against epithelial keratitis caused by herpes simplex (HSV) types 1 and 2, certain adenoviruses, vaccinia, and CMV. It is sold under the brand name Viroptic, and its chemical name is αα α –trifluorothymidine.
- Medical UsesTrifluridine is used in treating herpes infection of the eye. It is noteworthy that the herpes virus does not manifest itself in the body until an outbreak is triggered. Trifluridine is not a cure for HSV infection, but treatment of an outbreak can expedite the healing of sores in the eye and minimize the risk of complications such as vision loss.
- Side EffectsCommon side effects of trifluridine eye drops include temporary mild burning, irritation, and stinging. Chronic side effects include eye pain/redness, swelling eyelids, feeling as if there is a foreign object in the eye, and persistent blurred vision. Serious allergic reactions include itching, rash, severe dizziness, and troubled breathing.
- Indications and DosageTrifluridine ophthalmic solution is indicated for the treatment of recurrent epithelial keratitis and primary keratoconjunctivitis.
1% of trifluridine ophthalmic solution is instilled into the cornea of the affected eye every 2 hours while awake for a maximum daily dosage of the nine drops. This should be done until the complete re-epithelialization of the corneal ulcer. After re-epithelialization, there should be a treatment for 7 days of one drop every 4 hours.
Other forms of therapy should be considered if re-epithelialization has not occurred or if there are no signs of improvement after 7 days of treatment. Due to potential ocular toxicity, trifluridine ophthalmic solution should not be administered for periods exceeding 21 days.
- PrecautionsIt is important to inform the doctor or physician if one is allergic to trifluridine before using it. Trifluridine ophthalmic solution may contain other inactive ingredients that can lead to allergic reactions or other complications. Also, inform the doctor regarding your medical history, especially if you have previous eye problems. It is not safe to use machinery after applying the drug as it may impair one's vision. The medication should only be used when necessary in case of pregnancy.
- Drug InteractionsDo not start, change, or stop trifluridine ophthalmic solution medication before checking with the doctor. It is essential to inform the doctor if you are using any other form of herbal medicine.
- Mechanism of ActionTrifluridine ophthalmic solution is a nucleotide analogue, which is similar enough to be integrated into viral DNA replication. However, the –CF3 group added to the uracil component blocks base pairing, therefore interfering with viral DNA replication.
- Chemical PropertiesWhite to Off-White Solid
- OriginatorTrifluorothymidine ,Mann,W. Germany,1975
- Usesanti-herpesvirus antiviral agent
- UsesTrifluridine is used as antiviral agent in ophthalmie preparations.
- DefinitionChEBI: A pyrimidine 2'-deoxyribonucleoside compound having 5-trifluoromethyluracil as the nucleobase. An antiviral drug used mainly in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis.
- IndicationsTrifluridine (Viroptic) is a fluorinated pyrimidine nucleoside that has in vitro activity against HSV-1 and HSV- 2, vaccinia, and to a lesser extent, some adenoviruses. Activation of trifluridine requires its conversion to the 5 monophosphate form by cellular enzymes.Trifluridine monophosphate inhibits the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by thymidylate synthetase. In addition, it competes with deoxythymidine triphosphate (dTTP) for incorporation by both viral and cellular DNA polymerases. Trifluridine-resistant mutants have been found to have alterations in thymidylate synthetase specificity.
- Manufacturing ProcessA suspension of 4.00g (6.75 mmol) of 3',5'-bis-O-(p-nitrobenzoyl)-2'-deoxy-5-
(trifluoromethyl)uridine in 250 ml of methanol was treated with 10 ml of
diisopropylamine and refluxed until it had dissolved (about 18 minutes), and
the solution was concentrated. The dry residue was partitioned between 50 ml
of chloroform and 50 ml of water. The chloroform layer was washed with 20
ml of water, and the combined aqueous layers were concentrated. A low
ultraviolet extinction (ε 7200 and 262 μm; pH 1) and the presence of
isopropyl signals in the NMR spectrum (two singlets at γ8.73 and 8.85)
indicated the dry residue contained diisopropylamine, probably as a salt with
the relatively acidic heterocyclic N-H in 14.
A solution in 75 ml of water was treated with 8 ml (volume of resin) of Dowex 50 (H), prewashed with water and methanol. The resin was removed on a filter and washed with 25 ml of methanol and 50 ml of water, The combined filtrate was evaporated in vacuo to form 1.99 g of 2'-deoxy-4- (trifluoromethyl)uridine (100%), melting point 171°C to 175°C.
- brand nameViroptic (Monarch).
- Therapeutic FunctionAntiviral (ophthalmic)
- General DescriptionTrifluridine, 5-trifluoromethyl-29-deoxyuridine (Viroptic),is a fluorinated pyrimidine nucleoside that demonstrates invitro inhibitory activity against HSV-1 and HSV-2, CMV,vaccinia, and some adenoviruses.Trifluridine possesses atrifluoromethyl group instead of an iodine atom at the 5-position of the pyrimidine ring.
synthetase, and the biologically generated triphosphatecompetitively inhibits thymidine triphosphate incorporationinto DNA by DNA polymerase. In addition, trifluridine inits triphosphate form is incorporated into viral and cellularDNA, creating fragile, poorly functioning DNA.Trifluridine is approved in the United States for the treatmentof primary keratoconjunctivitis and recurrent epithelialkeratitis caused by HSV types 1 and 2. Topical trifluridineshows some efficacy in patients with acyclovir-resistantHSV cutaneous infections.
- Pharmaceutical ApplicationsTrifluorothymidine. A synthetic halogenated pyrimidine
nucleoside, first synthesized as an antitumor agent. It inhibits
enzymes of the DNA pathway and is incorporated into both
cellular and progeny viral DNA, causing faulty transcription of
late messenger RNA and the production of incompetent virion
protein. It does not require a viral thymidine kinase for monophosphorylation
and is far less selective and more toxic than
other analogs. It is active against HSV-1 and HSV-2, vaccinia
virus, CMV and possibly adenovirus. When applied as a 1%
ophthalmic solution, it rapidly enters the aqueous humor of
HSV-infected rabbits’ eyes but is cleared within 60–90 min.
It causes sister chromatid exchange – an indicator of mutagenicity – at 0.5 mg/L in human lymphocytes and fibroblasts. It is teratogenic to chick embryos when injected directly into the yolk sac. Its principal adverse effects in humans following systemic administration include leukopenia, anemia, fever and hypocalcemia. Accordingly, it is restricted to topical ophthalmic use in HSV ocular infections. The ophthalmic 1% aqueous solution produces occasional punctate lesions; other side effects are similar to those of idoxuridine but arise less frequently.
- Mechanism of actionTrifluorothymidine is a fluorinated pyridine nucleoside structurally related to idoxuridine. It has been approved by the U.S. FDA and is a potent, specific inhibitor of replication of HSV-1 in vitro. Its mechanism of action is similar to that of idoxuridine. Like other antiherpes drugs, it is first phos-phorylated by thymidine kinase to mono-, di-, and triphosphate forms, which are then incorporated into viral DNA in place of thymidine to stop the formation of late virus mRNA and subsequent synthesis of the virion proteins.
- Pharmacokinetics Trifluorothymidine, when given IV, shows a plasma half-life of 18 minutes and is excreted in the urine either unchanged or as the inactive metabolite 5-carboxyuracil.
- Clinical UseTrifluridine is administered as a topical ophthalmic solution for the treatment of primary keratoconjunctivitis and recurrent keratitis due to HSV-1 or HSV-2. It is not effective in the prophylaxis of these infections; however, it is effective in treating patients who were unresponsive or intolerant to topical idoxuridine or vidarabine.
- Side effectsThe most frequent adverse reactions to trifluridine administration
are transient burning or stinging and
palpebral edema. Other adverse reactions include superficial
punctate keratopathy, epithelial keratopathy,
hypersensitivity, stromal edema, irritation, keratitis
sicca, hyperemia, and increased intraocular pressure.
Trifluridine is mutagenic in vitro and carcinogenic and teratogenic when administered subcutaneously to animals. Topical trifluridine was not teratogenic in animal studies. Because it is applied topically in humans, the likelihood of systemic effects is low.
- Chemical SynthesisTrifluridine, 5-trifluoromethyl-1-(2-deoxyribofuranosyl)pyrimidin-2,
4-(1H.3H)-dione (36.1.22), is synthesized from 5-trifluoromethyluracil. This is synthesized
by the following scheme. It begins with trifluoroacetone, from which the oxynitrile (36.1.16)
is synthesized. Acetylation of this product gives the corresponding trifluoroacetate (36.1.16).
Pyrrolysis of this compound gives trifluoromethylacrylonitrile (36.1.17). Adding to this dry
hydrogen bromide in methanol solution in a process of which methanolysis of the nitrile
group takes place the bromide 36.1.19 is obtained, which upon acidic hydrolysis undergoes
heterocyclization to the dihydropyrimidine 36.1.20. Brominating of the obtained dihydropyrimidine with molecular bromine and subsequent dehydrobromination of the resulting product 36.1.21 on heating in dimethylformamide gives 5-trifluoromethyluracil (36.1.22). This is
reacted with 2-deoxy-D-ribos-1-phosphate using the nucleoside phosphorylase enzyme, or
by treating it with hyxamethyldisylazane and then with trichloromethylsilane to make 2,4-
trimethylsilyloxy-5-trifluoromethyl pyrimidine (36.1.23).
Hexamethyldisilazane, which itself does not form trimethylsilyl ethers, is used because using a combination of two reagents leads to optimal yield of trimethylsilyl ethers. Reacting the resulting pyrimidine derivative with 3,5-bis-(4-nitrobenzoate)-2-deoxyribofuranosyl chloride in the presence of mercury (II) acetate makes the corresponding ditrimethylsilyloxy nucleoside, which when treated with an aqueous solution of potassium iodide to remove the protecting groups. The resulting product undergoes preliminary purification by chromatography, and then is treated with a methanol solution of diisopropylamine to remove the 4-nitrobenzoyl protection from the furanosyl part, giving the desired trifluridine.
- Veterinary Drugs and TreatmentsTrifluridine (trifluorothymidine; Viroptic?) is a pyrimidine nucleoside analog. It is structurally related to 2-deoxythymidine, the natural precursor of DNA synthesis. Trifluridine is poorly absorbed by the cornea and is virostatic. Viroptic? interrupts viral replication by substituting “nonsense” pyrimidine analogues. For this reason, a competent surface immunity is necessary to resolve ocular disease, with or without antiviral therapy. A recent in vitro study in which several strains of feline herpes virus were collected from the United States and were used to infect kidney epithelial cells showed that trifluridine was more effective at lower concentrations compared with several other agents. For this reason, trifluridine was the first choice drug employed in the treatment of feline herpes virus ocular disease for many years. Because of the topical toxicity associated with use of trifluridine in cats, its popularity has diminished greatly. In many milder cases, the irritation associated with topical trifluridine is more intense then the inflammation induced by viral infection. Antiviral agents have also been used in the treatment of superficial punctate keratitis in the horse, thought to be associated with equine herpes virus-2 (EHV-2) infection of the cornea.
- Gemcitabine 1,2,3-Triacetyl-5-deoxy-D-ribose Gemcitabine hydrochloride L-Uridine 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE (TRIFLURIDINE) 5-Carboxy-2'-deoxyuridine 5-TRIFLUOROMETHYL 2'-DEOXYURIDINE, [2-14C]- 3'-O-benzyl-2'-deoxy-5-trifluoromethyluridine 5-(TRIFLUOROMETHYL)-URIDINE 5-TRIFLUOROMETHYL 2'-DEOXYURIDINE, [2'-3H]- 5-TRIFLUOROMETHYL-2'-DEOXYURIDINE, [2-13C-1,3-15N]- 5-TRIFLUOROMETHYL 2'-DEOXYURIDINE, [6-3H]- Zidovudine 3-(Trifluoromethyl)benzaldehyde Trifluoromethyl Fluorocytosine (Trifluoromethyl)trimethylsilane 1-beta-D-Arabinofuranosyluracil
- Company Name:Shanghai YuLue Chemical Co., Ltd. Gold
- Tel:021-13671753212 13917602471 021-60345187
- Company Name:Lihan (Shanghai) Biotechnology Co., Ltd. Gold
- Company Name:Shanghaizehan biopharma technology co., Ltd. Gold
- Company Name:Shanghai Boyle Chemical Co., Ltd.
- Company Name:J & K SCIENTIFIC LTD.
- Tel:400-666-7788 010-82848833-