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Anti-infective Agents 297
Properties: Idoxuridine occurs as a white to slightly beige color crystalline powder. It is soluble
in water, methanol, ether, chloroform, acetone, ethyl acetate and dioxane. Its melting point is
194°C.
Mechanism of Action: The primary action of idoxuridine closely resembles to thymidine and
consists of inhibiting viral DNA replication. Idoxuridine is incorporated in place of thymidine
into viral DNA, resulting in faulty DNA and the inability to infect or destroy tissue or to
reproduce. Idoxuridine upon ocular administration converted to its mono-, di-, and triphosphate
forms, then incorporated into DNA and disrupts viral replication.
Uses:
➢ Idoxuridine is used to slow the growth of herpes viruses that cause certain eye infections.
➢ This drug comes in solution form to be instilled into the eye.
➢ For prescription drug, it comes as 0.1% ophthalmic solution/drops (Herplex and
Dendrid). Various side-effects of the eye drops include irritation, blurred vision and
photophobia.
➢ It is used for the treatment of simplex keratitis and eye infection in the cornea caused by
the herpes simplex virus.
➢ The ophthalmic ointment form of this medicine is used to treat the lesions due to simplex
keratitis epithelial infection.
Dosage: 0.5% ophthalmic ointment or as a 0.1% ophthalmic solution.
Storage: Store Idoxuridine at room temperature in a tight, light-resistant container. Protect it
from exposure to light. Store between 8°C to 15°C. Store in a collapsible ophthalmic ointment
tube.
Officials:
➢ Idoxuridine, I.P.
➢ Idoxuridine Eye Drop, I.P.
11.4.3 Acyclovir
Brand Names: Sitavig, Xerese, Zovirax
Acyclovir is a synthetic analogue of the purine nucleoside derived from guanine. It has potent
antiviral activity against the herpes simplex virus (HSV) and varicella-zoster virus by interfering
with DNA synthesis. After conversion in vivo to the active metabolite by thymidine kinase into
acyclovir triphosphate, acyclovir competitively inhibits viral DNA polymerase, thereby inhibiting
viral replication.
298 Text Book of Pharmaceutical Chemistry
IUPAC Name: 2-amino-9-(2-hydroxyethoxymethyl)-1H-purin-6-one
Properties: Acyclovir occurs as white to light yellow crystalline powder with a maximum
solubility in water at 22°C to 25°C and solubility ranges from 1.2 to 1.6 mg/mL. The solubility of
the drug varies slightly with pH and lowest solubility of 2.3 mg/mL reported at pH 5.8 at 37°C.
Uses:
➢ Acyclovir is used to treat infections caused by certain types of viruses. It treats cold
sores around the mouth (caused by herpes simplex virus), shingles (caused by herpes
zoster), and chickenpox.
➢ It is used to treat encephalitis (inflammation of the brain).
➢ It may also help to treat pain associated with an outbreak of genital herpes after the sores
heal.
Dosage Forms: Acyclovir is also available as a capsule, suspension, and buccal tablet that you
take by mouth. It may be administered intravenously, orally, or topically.
➢ Oral suspension: 200 mg/5 ml
➢ Tablet: 400 mg, 800 mg
➢ Capsule: 200 mg
➢ Injection: 500 mg/vial, 1000 mg/vial
Storage and Stability: Tablets should be stored at controlled room temperature (15°C to 25°C)
in a dry place and protected from light. Suspension should be stored at controlled room
temperature (15°C to 25°C).
11.4.4 Foscarnet
Brand Names: Foscavir, Phosphonoformic acid
Foscarnet is a pyrophosphate analogue of phosphonoacetic acid that inhibits all HHVs. The
structural formula is:
IUPAC Name: Phosphonoformic acid
Properties: Foscarnet is a white, crystalline powder; Foscavir is the brand name for Foscarnet
Sodium. The chemical name of Foscarnet Sodium is Phosphonoformic Acid and Trisodium Salt.
Foscarnet sodium is a white, crystalline powder containing 6 equivalents of water of hydration.
Anti-infective Agents 299
Mechanism of Action: Foscarnet is an analogue of pyrophosphate, exerts its antiviral activity by
a selective inhibition at the pyrophosphate binding site on virus-specific DNA polymerases (or
reverse transcriptase). After binding, the drug blocks the cleavage of the pyrophosphate moiety
from deoxynucleotide triphosphates, in turn halting DNA chain elongation.
Uses:
➢ It is used as an antiviral agent in the treatment of cytomegalovirus retinitis (CMV
retinitis, and herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2), in inflammation
of the retina that can lead to blindness).
➢ Foscavir injection is a sterile, isotonic aqueous solution for intravenous administration
only.
➢ Foscarnet sodium injection is indicated for the treatment of CMV retinitis in patients with
acquired immunodeficiency syndrome (AIDS).
Dosage Forms: Intravenous solution (24 mg/mL). Each ml of foscavir contains 24 mg of
Foscarnet sodium hexahydrate in water for injection. Due to its high polarity and low oral
absorption, Foscarnet is given intravenously.
11.4.5 Zidovudine
Brand Names: Combivir, Retrovir, Trizivir
Zidovudine is a synthetic dideoxynucleoside. It is an analogue of thymidine that inhibits
replication of the AIDS virus. It can block nucleic acid synthesis such as purine and pyrimidine
nucleoside analogs, and are proven antibacterial, antiviral, and anticancer agents. The structural
formula of Zidovudine is:
IUPAC Name: 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-
dione
Properties: Zidovudine occurs as a white to beige, odourless, crystalline solid with a molecular
weight of 267.24 and a solubility of 20.1 mg per ml in water at 25°C. The molecular formula is
C
10
H
13
N
5
O
4
.
Uses:
➢ Zidovudine is an antiretroviral medication used to prevent and treat HIV/AIDS.
➢ It is used to prevent mother-to-child transmission of HIV.
➢ It is given to women with HIV during pregnancy and childbirth, and to their infants after
birth.
300 Text Book of Pharmaceutical Chemistry
Storage: Zidovudine tablets should be stored at room temperature (20-25°C), and capsules and
oral solution between (15- 25°C). Protect Zidovudine capsules from moisture.
Dosage Forms and Strengths:
➢ Tablets: 300 mg
➢ Capsules: 100 mg
➢ Syrup: 50 mg/5 ml
➢ Injection: Injection is a clear, nearly colorless, sterile aqueous solution with a pH of
approximately 5.5. Each vial contains 200 mg of Zidovudine in 20 ml solution (10 mg per
ml).
Marketed Preparations:
Drug
Brand Name
Company
Zidovudine Tablet I.P.
Zidovir- 300
Million Health Pharmaceuticals
Zidovudine and
Lamivudine Tablets I.P.
Zidolam
Lamivudine 150 mg +
Zidovudine 300 mg
Gandhi Medicos
11.4.6 Ribavirin
Brand Names: Copegus, Moderiba, Rebetol, RibaPak, Ribasphere, RibaTab
Ribavirin, a synthetic guanosine analogue, is a 1-ribosyltriazole, i.e., the 1-ribofuranosyl
derivative of 1,2,4-triazole-3-carboxamide. It is an inhibitor of HCV polymerase and possesses a
broad spectrum of activity against DNA and RNA viruses. The structural formula of Ribavirin is:
IUPAC Name: 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-
3-carboxamide
Properties: It occurs as colorless, odorless and tasteless white powder. Its melting point is 345°F
to 349°F. It exists in two polymorphic forms. It is soluble in water and slightly soluble in alcohol.
Anti-infective Agents 301
Uses:
➢ Ribavirin has a role as an antimetabolite, an antiviral agent, an anti-infective agent and an
anticorona viral agent.
➢ It is used in combination with other antiviral agents to treat chronic hepatitis C.
➢ It is used in viral infection of the liver.
Storage and Stability: Ribavirin tablets and capsules should be stored at room temperature,
between 68°F and 77°F (20°C to 25°C). Oral solution of Ribavirin should be stored at room
temperature, between 68°F and 77°F (20°C to 25°C), or in the refrigerator, between 36°F and
46°F (2°C to 8°C). Its solution contains no preservatives and is stable for 24 hours when stored
under sterile conditions at a room temperature of 20°C to 30°C.
Dosage Forms:
➢ Oral capsule (200 mg)
➢ Oral solution (40 mg/mL)
➢ Oral tablet (200 mg, 200-400 mg, 400 mg, 400-600 mg, 600 mg)
Marketed Preparations:
Drug
Brand Name
Company
Ribavirin Capsules
Ribavin 200
Wellona Pharma Pvt. Ltd.
Ribavirin 200 mg
Ribamune Capsule
Cipla Limited
11.4.7 Remdesivir
Brand Name: Veklury
Remdesivir is a broad-spectrum antiviral drug with potent in vitro antiviral activity against a
various panel of RNA viruses such as Ebola virus, MERS-CoV and SARS-CoV. It acts as an
inhibitor of the viral RNA-dependent RNA polymerase (RdRP). It is a prodrug whose major
active metabolite is GS-441524. Its 1'-CN group and C-linked nucleobase ensure optimal anti-
Ebola potency and selectivity against host polymerase enzymes.
It has broad-spectrum activity against several viral families such as filoviruses, paramyxo
viruses, and corona viruses, including the SARS and MERS corona viruses (CoVs).
302 Text Book of Pharmaceutical Chemistry
IUPAC Name: 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-
yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
Uses:
➢ Remdesivir is an RNA polymerase inhibitor with potent antiviral activity.
➢ It is used for the treatment of corona virus disease (COVID-19) in adults and adolescents
with pneumonia requiring supplemental oxygen.
➢ It is originally developed to treat hepatitis C.
Dosage Forms and Strengths:
➢ Intravenous powder for injection (100 mg); intravenous solution (5 mg/mL)
➢ Injection, lyophilized powder for reconstitution – 100 mg/vial
➢ Injection, concentrated solution – 100 mg/20 ml (5 mg/mL)
Marketed Preparations:
Drug
Brand Name
Company
Remdesivir 100 mg
Remivir
Cipla Limited
Remdesivir injection 100 mg
Jubi R Injection
Jubilant Life Sciences
11.4.8 Favipiravir
Brand Name: Avigan
Favipiravir is a drug of the class pyrazines, i.e., is pyrazine substituted by aminocarbonyl,
hydroxyl and fluoro groups at positions 2, 3 and 6, respectively. It is a pyrazine carboxamide
derivative with activity against RNA viruses.
IUPAC Name: 5-fluoro-2-oxo-1H-pyrazine-3-carboxamide
Properties: It occurs as light yellow to yellow solid. Its melting point is 187-193°C. It is slightly
soluble in water.
Uses:
➢ Favipiravir is an antiviral medication used to treat influenza.
➢ It is also being studied to treat a number of other viral infections, including
SARS-CoV-2.
Anti-infective Agents 303
➢ It also inhibits influenza strains resistant to current antiviral drugs, and shows a
synergistic effect in combination with Oseltamivir.
➢ Favipiravir not only inhibit replication of influenza A and B, but the drug has shown
promise in the treatment of avian influenza.
➢ Favipiravir has been investigated for the treatment of life-threatening pathogens such as
Ebola virus, Lassa virus, and now COVID-19.
11.5 ANTIMALARIAL AGENTS
Introduction
Malaria is a disease caused by plasmodium parasite. Humans are infected with the parasite
after being bitten by infected female anopheles mosquitoes. Once the parasites transfer into the
body, they travel to the liver, where they mature. After several days, the mature parasites enter the
bloodstream and begin to infect red blood cells. The parasites inside the red blood cells grow in
48 to 72 hours, forcing the infected cells to burst open. The parasites continue to infect red blood
cells, causing symptoms that come and go in two- to three-day cycles. People who have malaria
usually feel very sick with a high fever and shaking chills.
Causative Agents
There are mainly four types of malaria parasites that can infect humans: Plasmodium vivax,
P. ovale, P. malariae, and P. falciparum. Out of these four types of parasites, P. falciparum
causes a more severe form of the disease and those who contract this form of malaria have a
higher risk of death.
Classification of Antimalarial Agents
Antimalarial agents can be classified according to chemical structure and antimalarial
activity:
I. Chemical Classification of Antimalarial Agents
➢ Aryl amino alcohols: Quinine, Quinidine mefloquine, Halofantrine.
➢ 4-aminoquinolines: Chloroquine, Hydroxychloroquine, Amodiaquine.
➢ Folate synthesis inhibitors:
Type 1 – competitive inhibitors of dihydropteroate synthase – Sulphones, Sulphonamides.
Type 2 – inhibit dihydrofolate reductase-biguanides like Proguanil and Chloroproguanil;
and diaminopyrimidines like Pyrimethamine.
➢ 8-aminoquinolines: Primaquine.
➢ Antimicrobials: Tetracycline, Doxycycline, Clindamycin, Azithromycin,
Fluoroquinolones.
➢ Peroxides: Artemisinin derivatives and analogues – Artemether, Arteether, Artesunate,
Artelinic acid.
304 Text Book of Pharmaceutical Chemistry
➢ Naphthoquinones: Atovaquone.
➢ Iron chelating agents: Desferrioxamine.
II. Classification of Antimalarial Agents According to Antimalarial Activity
➢ Tissue schizonticides for causal prophylaxis: These drugs act on the primary tissue
forms of the plasmodia, which after growth within the liver, initiate the erythrocytic
stage, e.g., Pyrimethamine and Primaquine.
➢ Tissue schizonticides for preventing relapse: These drugs act on the hypnozoites of
P. vivax and P. ovale in the liver that cause relapse of symptoms on reactivation, e.g.,
Primaquine is the prototype drug and Pyrimethamine.
➢ Blood schizonticides: These drugs act on the blood forms of the parasite and thereby
terminate clinical attacks of malaria, e.g., Chloroquine, Quinine, Mefloquine,
Halofantrine, Pyrimethamine, Sulfadoxine, Sulfones, Tetracyclines, etc.
➢ Gametocytocides: Gametocidal drugs destroy the sexual forms of the parasite in the
blood and thereby prevent transmission of the infection to the mosquito. Chloroquine and
Quinine have gametocytocidal activity against P. vivax and P. malariae, but not against
P. falciparum. Primaquine has gametocytocidal activity against all plasmodia, including
P. falciparum.
➢ Sporontocides: These drugs prevent the development of oocysts in the mosquito and thus
ablate the transmission, e.g., Primaquine and Chloroguanide.
11.5.1 Quinine Sulphate
Brand Name: Qualaquin, QM-260, Quinamm
Quinine sulphate is the sulphate of a natural substance, quinine, obtained from the bark of
various species of Cinchona. It is first isolated in 1820 from the bark of a Cinchona tree, which is
native to Peru.
Chemistry and Structure: Chemically Quinine Sulphate described as cinchonan-9-ol,
6'-methoxy-, (8&apha,9R)-, sulphate (2:1) (salt), dihydrate with a molecular formula of
(C
20
H
24
N
2
O
2
)
2
•H
2
SO
4
•2H
2
O. The structural formula of quinine sulphate is:
Nomenclature: (8S, 9R)-6-methoxy-4-quinolenyl-5-vinyl-2-quinuclidinyl methanol sulfate
dihydrate, quinine sulfate.
Anti-infective Agents 305
Properties: It occurs as fine, white, needle-like crystals, usually lustreless, making a light and
readily compressible mass. It is slightly soluble in water at 25°C, sparingly soluble at 100°C,
slightly soluble in ethanol at 25°C, soluble at 80°C, slightly soluble in chloroform and practically
insoluble in ether.
Uses: This medication is used to treat malaria caused by mosquito bites. It is used to kill the
malaria parasites living inside red blood cells.
Dosage Forms and Strengths: It is supplied for oral administration as capsules containing 324
mg capsules – hard gelatin of the active ingredient quinine sulfate USP, equivalent to 269 mg free
base. Inactive ingredients: corn starch, magnesium stearate, and talc.
Storage: Store at 20°C to 25°C. Keep away from light and moisture. Keep all medicines away
from children and pets. Do not flush medications down the toilet or pour them into a drain unless
instructed to do so. Properly discard this product when it is expired or no longer needed.
Officials:
➢ Quinine Sulphate, I.P.
➢ Quinine Sulphate Tablet, I.P.
11.5.2 Chloroquine Phosphate
Brand Names: Aralen Phosphate, Aralen Hydrochloride
The chloroquine is an aminoquinoline derivative that is quinoline which is substituted at
position 4 by a [5-(diethylamino) pentan-2-yl] amino group at position 7 by chlorine. Chloroquine
phosphate is used for the treatment and prevention of malaria and amebiasis. It is a drug of class
called antimalarials and amebicides. It works by killing the organisms that cause malaria.
Quinoline phosphate has the following structural formula:
Nomenclature: Chemically, it is 7-chloro-4-[4- (diethylamino)-1-methylbutyl]amino
Properties: It occurs as white to slightly yellow, crystalline powder. It is odorless and has bitter
taste. It is freely soluble in water; less soluble in neutral or alkaline pH; and practically insoluble
in alcohol, chloroform and ether.
306 Text Book of Pharmaceutical Chemistry
Uses:
➢ Chloroquine phosphate is used for the treatment of malaria, hepatic amoebiasis and lupus
erythematosus.
➢ It is used in light-sensitive skin eruptions and rheumatoid arthritis.
➢ It has a role as an antirheumatic drug, a dermatologic drug, an autophagy inhibitor and an
anticorona viral agent.
➢ It is indicated for the treatment of amebic liver abscess, usually in combination with and
effective intestinal amebicide.
Dosage Form: The dosage of chloroquine phosphate is often expressed in terms of equivalent
chloroquine base. Chloroquine Phosphate, U.S.P. is available as tablets containing either 250 or
500 mg of diphosphate. In infants and children, the dosage is preferably calculated by body
weight.
Storage: Store at room temperature (15°C to 25°C). Protect from light. Product in powder form is
stable for 6 months at room temperature when properly stored.
Officials:
➢ Chloroquine Phosphate, I.P.
➢ Chloroquine phosphate Injection, I.P.
➢ Chloroquine phosphate Tablet, I.P.
➢ Chloroquine Syrup, I.P.
11.5.3 Primaquine Phosphate
Brand Name: Primaquine
Nomenclature: N4-(6-methoxyquinolin-8-yl) pentane-1,4-diamine; bis(phosphoric acid)
Primaquine Phosphate is the phosphate salt form of primaquine. It is an 8-aminoquinoline
derivative with antimalarial activity. This drug is used for the treatment of malaria, specifically
when infection caused due to Plasmodium vivax and Plasmodium ovale.
Properties: It occurs as orange-red crystalline solid soluble in water. It is a dibasic compound,
having pKa values of 3.2 and 10.4. Primaquine phosphate shows stereoisomerism due to the
presence of a chiral carbon in the diamine side chain. It exists as both R(+) and S(–) enantiomers,
but only racemic preparations containing the racemic mixture are commercially available.