Nucleotide analogues

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Chapter: Medicinal Chemistry : Antiviral Agents

Nucleotide analogues : a. Purine nucleosides and nucleotides i. Acyclovir (Ocuvir, Zovirax, Cyclovir) ii. Ganciclovir (Ganguard) b. Pyrimidine nucleoside and nucleotide inhibitors iii. Idoxuridine (Antizona, Dendrid) iv. Methisazone (Marboran) d. Adamantane amines 1. Amantadine (Symmetrel) 2. Rimantadine Miscellaneous i. Ribavirin (Virazole)


Antiviral Agents - Synthesis and Drug Profile

Nucleotide analogues

a. Purine nucleosides and nucleotides

 

i. Acyclovir (Ocuvir, Zovirax, Cyclovir)


Synthesis


Metabolism: The bioavailability of acyclovir is 15%–30 % and it is metabolized to 9-carboxy-methoxymethyl guanine, which is inactive.

Properties and uses: Acyclovir is a white crystalline powder, slightly soluble in water, soluble in dimethyl sulphoxide and in dilute mineral acids and alkali hydroxides, and very slightly soluble in ethanol. It is a purine nucleoside analogue, used as antiviral agent against herpes viruses.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically. Perform a blank titration.

Dose: For herpes virus infections the administered dose for immuno-suppressed patients is up to 10 mg/kg body weight every 8 h.

Dosage forms: Acyclovir cream B.P., Acyclovir eye ointment B.P., Acyclovir intravenous infusion B.P., Acyclovir oral suspension B.P., Acyclovir tablets B.P., Dispersible acyclovir tablets B.P.

Metabolism of Valacyclovir: The related analogue 6-deoxy acyclovir is a prodrug form of acyclovir that is activated through metabolism by xanthine oxidase.

Metabolism of Cidofovir: It is metabolized by phosphorylation and it gives cidofovir diphosphate.

Metabolism of Famciclovir: It is a prodrug of penciclovir, which is formed in vivo by hydrolysis of acetyl groups and oxidation at the 6th position by the mixed function oxidase. Penciclovir and its metabolite penciclovir triphosphate posseses antiviral activity.


Metabolism of vidarabine: It is deaminated rapidly by adenosine deaminase enzyme, which is present in the serum and the red blood cells. The enzyme converts vidarabine to its principal metabolite, arabinosyl hypoxanthine, which has weak antiviral activity.


Uses: It is used for the short-term treatment of herpes simplex and chicken pox caused by varicella-zoster virus (VZV).

 

ii. Ganciclovir (Ganguard)


Synthesis


Properties and uses: Ganciclovir is a white powder, soluble in water and it is used as an antiviral agent.

Dose: The recommended dose is 5 mg/kg 1 h for infusion every 12 h for 14 days.

 

b. Pyrimidine nucleoside and nucleotide inhibitors

 

iii. Idoxuridine (Antizona, Dendrid)


Synthesis


Metabolism: It has a plasma half-life of 30 min and it is rapidly metabolized in the blood to idoxuracil and uracil.

Properties and uses: Idoxuridine is a white crystalline powder, slightly soluble in water and in alcohol. It dissolves in dilute solutions of alkali hydroxides. It is a pyrimidine nucleoside analogue and used as an antiviral agent against herpes virus .

Assay: Dissolve the sample in dimethylformamide and titrate with 0.1 M tetrabutyl ammonium hydroxide. Determine the end point potentiometrically.

Dose: The administered dose topically as a ointment is 0.5%, 4–16 times a day or 0.1 ml of a 0.1% solution every 1 to 2 h into the conjunctiva.

Dosage forms: Idoxuridine eye drops B.P.

 
c. Thiosemicarbazones

 

iv. Methisazone (Marboran)


Synthesis


Dose: The recommended oral dose is 1.5–3.0 g twice daily for four days. As a prophylactic against small pox, it should be administered before the 8th or 9th day of the 12-day incubation period.

Uses: Used in the treatment of viral infection.

 

d. Adamantane amines

 

1. Amantadine (Symmetrel)


Synthesis


Metabolism: Approximately, 90% of the drug is excreted unchanged by the kidney, primarily through glomerular filtration and tubular secretion, and there are no reports of metabolic products. Acidification of urine increases the rate of amantadine excretion.

Properties and uses: Amantadine hydrochloride is a white crystalline powder, soluble in water and in alcohol. Amantadine is used in the treatment of Parkinson’s disease. It is effective against influenza type-A virus, para influenza, and some RNA virus. It is also used as a dopamine receptor agonist.

Assay: Dissolve the sample in a mixture of 0.01 M hydrochloric acid and alcohol (1:10) and titrate with 0.1 M sodium hydroxide. Determine the end point potentiometrically.

Dose: The usual recommended dose is 100 mg twice daily. For children 1–9 years of age the administered dose is 4–9 mg/kg and 9–12 years of age 100 mg twice daily.

Dosage forms: Amantadine capsules I.P., B.P., Amantadine oral solution B.P.

 

2. Rimantadine


Synthesis


Metabolism: Rimantadine is metabolized in the liver and approximately 20% is excreted unchanged as hydroxylated compound.

Properties and uses: Rimantadine is a white to off-white crystals, soluble in water. It is used for the prevention of infection caused by various strains of influenza virus-A.

Dose: The recommended dose usually is 300 mg.

 

Miscellaneous

i. Ribavirin (Virazole)


1-(3,4-Dihydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboxamide

Synthesis


Properties and uses: Ribavirin is a white crystalline powder, soluble in water, slightly soluble in ethanol and in methylene chloride. It is used in the treatment of influenza type-A and -B, hepatitis, genital herpes, and Lassa fever.

Assay: It is assayed by adopting liquid chromatography technique.

Dose: For viral hepatitis, influenza, and herpes virus infections, the recommended dose is up to 1g per day in divided doses.

Dosage forms: Ribavirin nebulizer solution B.P.

 

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