Idoxuridine

Absorption

Systemic absorption is unlikely following ocular administration even when nasolacrimal secretions are swallowed, since vidarabine is rapidly deaminated in the gastrointestinal tract.

Toxicity

Hypersensitivity or increased sensitivity of eyes to light. LD50=3080 mg/kg (orally in mice).

Description

5-Iodo-2'-deoxyuridine is a nucleoside analog that inhibits the replication of viruses and other DNA-containing organisms. 2'-Deoxy-5-iodouridine also has inhibitory properties on cell nuclei, which may be due to its ability to bind with DNA and prevent the synthesis of RNA or protein.

Description

Idoxuridine is an iodinated analogue of the nucleosides deoxyuridine and thymidine. It was first synthesized by William H. Prusoff at Yale University?(New Haven, CT) in 1958. Five years later, it became the first antiviral drug approved by the US Food and Drug Administration, for topical use against herpes simplex keratitis.
Idoxuridine in solution or ointment form also has ophthalmic applications. It cannot be administered internally because it is cardiotoxic.
If idoxuridine is the oldest antiviral, what is the newest? One candidate is lufotrelvir1, a compound disclosed in 2020 by researchers at multiple laboratories of Pfizer Worldwide Research and Development and other institutions. Lufotrelvir is a potential treatment for COVID-19, although, unlike some others, it must be administered intravenously. This month, Robert A. Singer and co-workers at Pfizer (Groton, CT) reported an improved synthesis of the relatively unstable lufotrelvir.
1. CAS Reg. No. 2468015-78-1.

Chemical properties

Crystalline Solid

Originator

Dendrid,Alcon,US,1963

The Uses of Idoxuridine

5-Iodo-2'-deoxyuridine is antitumor nucleoside enantiomer thymidine kinase used as potential antiviral agents.

The Uses of Idoxuridine

Antiviral;Nucleic acid synthesis inhibitors

The Uses of Idoxuridine

Idoxuridine is an antiviral agent effective against herpes-simplex infections; in ophthalmie eyedrops, ointments, and solutions.

Indications

For use in keratoconjunctivitis and keratitis caused by herpes simplex virus.

Definition

ChEBI: A pyrimidine 2'-deoxyribonucleoside compound having 5-iodouracil as the nucleobase; used as an antiviral agent.

Background

An analog of deoxyuridine that inhibits viral DNA synthesis. The drug is used as an antiviral agent.

What are the applications of Application

Idoxuridine is a cytotoxic analog of thymidine, antiviral

Indications

Idoxuridine (Herplex) is a water-soluble iodinated derivative of deoxyuridine that inhibits several DNA viruses including HSV, VZV, vaccinia, and polyoma virus. The triphosphorylated metabolite of idoxuridine inhibits both viral and cellular DNA synthesis and is also incorporated into DNA. Such modified DNA is susceptible to strand breakage and causes aberrant viral protein synthesis. Because of its significant host cytotoxicity, idoxuridine cannot be used to treat systemic viral infections. The development of resistance to this drug is common.

Manufacturing Process

5 g of 5-iodo-uracil (obtained according to T.B. Johnson et al., J. Biol. Chem. 1905/6, 1, 310) in 15 cc of acetic anhydride are heated under reflux for 4,5 hours. The acetylated derivative crystallizes on cooling. The crystallized product is chilled for ? hour then filtered with suction, washed with acetic anhydride and then with ether and dried. 4.5 g of 1-acetyl-5-iodo-uracil, MP 167°C, are thus obtained.
1.51 g of mercuric acetate are dissolved in 50 cc of methanol under reflux and 1.35 g of 1-acetyl-5-iodo-uracilare added. A white precipitate is soon formed. The reaction mixture is kept under reflux for % hour and then allowed to cool to room temperature. The precipitate is then filtered with suction, washed with methanol and dried.
2.1 g of monomercuric 5-iodo-uracil, MP 280°C, are thus obtained as a colorless powder, insoluble in water and the majority of the usual organic solvents, such as benzene, chloroform, alcohol, ether and acetone. 1.46 g of 5-iodo-uracil monomercuric derivative are introduced into 50 cc of chloroform and 20 to 30 cc of the solvent are distilled off under normal pressure to ensure good dehydration of the reaction medium. The mixture is cooled to room temperature and 2.59 g of 3,5-di-p-toluyl-desoxy-Dribofuranosyl chloride added. The mixture is agitated for 6 hours with glass balls, filtered, rinsed with chloroform and the filtrate is successively washed with an aqueous sodium iodide solution, with water, with a saturated solution of sodium bicarbonate and again with water. The product is dried over sodium sulfate, filtered and evaporated to dryness.
The residue crystallizes in ether and yields about 600 mg of β-3',5'-di-ptoluyl-2'-desoxy-5-iodo-uridine which is recrystallized from toluene. The product is obtained as colorless crystals, soluble in chloroform and pyridine, sparingly soluble in acetone, benzene ether and alcohol, insoluble in water, MP 193°C.
206 mg of 3',5'-di-p-toluyl-2'-desoxy-5-iodo-uridineare heated at 80°C with 2.5 cc of caustic soda solution (0.4 N) for ? hour. The solution obtained is cooled, filtered and then acidified with acetic acid. The desoxy-iodo-uridine and the p-toluic acid crystallize. Ether is added to dissolve the p-toluic acid, the mixture is chilled, filtered with suction, washed with water and ether, and dried. The residue is recrystallized from water and 100 mg of 5-iodo-2'- desoxy-uridine, are obtained.

brand name

Dendrid (Alcon); Herplex (Allergan); Stoxil (GlaxoSmithKline).

Therapeutic Function

Antiviral (ophthalmic)

Pharmaceutical Applications

A halogenated pyrimidine analog originally synthesized as an anticancer agent. Formulated in dimethylsulfoxide for topical application and as a solution for ophthalmic use.
Activity is largely limited to DNA viruses, primarily HSV-1, HSV-2 and VZV. HSV-1 plaque formation in BHK 21 cells is sensitive to 6.25–25 mg/L; type 2 microplaques required 62.5–125 mg/L. RNA viruses are not affected, with the exception of oncogenic RNA viruses such as Rous sarcoma virus. Drug resistance is easily generated in vitro, and may be an obstacle to treatment. However, there is little or no crossresistance with newer nucleoside analogs.
It is poorly soluble in water, and aqueous solutions are ineffective against infections other than those localized to the eye. In animals, therapeutic levels are achieved in the cornea within 30 min of ophthalmic application and persist for 4 h. Penetration is otherwise poor, with only the biologically inactive dehalogenated metabolite uracil entering the eye.
The drug is too toxic for systemic administration. Contact dermatitis, punctate epithelial keratopathy, follicular conjunctivitis, ptosis, stenosis and occlusion of the puncta and keratinization of the lid margins occur in up to 14% of those receiving ophthalmic preparations.
It is used in herpes keratitis, but has largely been superseded by trifluridine or aciclovir.

Biochem/physiol Actions

5-Iodo-2′-deoxyuridine prevents in vitro DNA viral replication. This is observed in herpesviruses and poxviruses It might possess teratogenic, tumor-promoting, mutagenic, and immunosuppressive properties. 5-Iodo-2′-deoxyuridine, used in topical applications, is effective against epithelial infections.

Mechanism of action

Idoxuridine is a nucleoside containing a halogenated pyrimidine and is an analogue of thymidine. It acts as an antiviral agent against DNA viruses by interfering with their replication based on the similarity of structure between thymidine and idoxuridine. Idoxuridine is first phosphorylated by the host cell virusencoded enzyme thymidine kinase to an active triphosphate form. The phosphorylated drug inhibits cellular DNA polymerase to a lesser extent than HSV DNA polymerase, which is necessary for the synthesis of viral DNA. The triphosphate form of the drug is then incorporated during viral nucleic acid synthesis by a false pairing system that replaces thymidine. When transcription occurs, faulty viral proteins are formed, resulting in defective viral particles.

Pharmacokinetics

In chemical structure idoxuridine closely approximates the configuration of thymidine, one of the four building blocks of DNA (the genetic material of the Herpes virus). As a result, idoxuridine is able to replace thymidine in the enzymatic step of viral replication or "growth". The consequent production of faulty DNA results in a pseudostructure which cannot infect or destroy tissue. In short, by pre-empting a vital building block in the genetic material of the Herpes simplex virus, Herplex-D topical solution destroys the infective and destructive capacity of the viral material. The virus infected cell may only be attacked during the period of active synthesis of DNA. This occurs early in the development of the Herpes simplex lesion, but at different times in different cells. Therefore, ideally, the affected area should remain saturated with the antiviral agent.

Clinical Use

The only FDA-approved use of idoxuridine is in the treatment of herpes simplex infections of the eyelid, conjunctiva conjunctiva, and cornea. It is most effective against surface infections because it has little ability to penetrate the tissues of the eye. intravenous idoxuridine was designated an orphan drug for the treatment of soft tissue sarcoma.

Side Effects

Idoxuridine may cause local irritation, mild edema, itching, and photophobia. Corneal clouding and small punctate defects in the corneal epithelium have been reported. Allergic reactions are rare.

Safety Profile

Moderately toxic by intraperitoneal route. Experimental teratogenic and reproductive effects. Questionable carcinogen with experimental carcinogenic data. Human mutation data reported. When heated to decomposition it emits very toxic fumes of Iand NOx.

Synthesis

Idoxuridine, 5-iodo-1-(2-deoxyyribofuranosyl)pyrimidin-2,4-(1H.3H)-dione (36.1.14), is synthesized by the following scheme. 5-Iodouracil is acylated with acetic anhydride to make 1-acetyl-5-iodouracil (36.1.11). Treating this with mercury(II) acetate gives 5-iodomonomercury uracil (36.1.12), which is reacted with 1-bromodidesoxy-D-ribofuranosyl-3,5-bis-(p-toluenesulfonate) to make a ditosyl derivative (36.1.13). Hydrolysis of the tosyl groups using sodium hydroxide and subsequent treatment of the resulting substance with acetic acid gives the desired product idoxuridine.

Veterinary Drugs and Treatments

Idoxuridine (IDU) is chemically similar to thymidine and its substitution into viral DNA causes misreading of the viral genetic code thereby inhibiting viral replication. Like trifluridine, IDU is considered virostatic rather than viricidal. IDU was found to be second to trifluridine in efficacy in vitro against common strains of feline herpes virus growing in kidney epithelial cells. IDU is extremely well tolerated in cats and this feature alone makes it the most popular antiviral currently available for use in cats with presumed or established feline herpes virus infection. Although trifluridine was shown to be more effective in vitro, the topical irritation it induces in cats frequently negates any beneficial effect that might be noted clinically. Stinging upon application is a rare feature with IDU/artificial tear preparations.

Metabolism

Idoxuridine is rapidly inactivated by deaminases or nucleotidases.

Metabolism

Idoxuridine is metabolized rapidly in the body to iodouracil, uracil, and iodide. Metabolites are excreted in the urine.