Antiviral Agents

ANTI-HIV AGENTS
Acquired immunodeficiency syndrome (AIDS) is caused by the retrovirus, human
immunodeficiency virus. The HIV infection, which targets the lymphocytes, the monocytes, and
macrophages expressing surface CD-4 receptors, eventually produces profound defects in cell-
mediated immunity. Over time, infection leads to severe depletion of CD-4 T-lymphocytes
resulting in opportunistic infection like tuber- culosis, fungal, viral, protozoal, and neoplastic
diseases, and ultimately death.

HIV—Virus Life Cycle

HIV is the retrovirus of the lentiviridae family, originally referred to as HTLV-III. HIV virus
consists of outer lipid bilayer the surface of which contains gp120 (glycoprotein). Nucleocapsid
contains single-stranded RNA. Figs. 29.1 and 29.2 in the coloured set of pages).
The gpl20 has a greater affinity for CD-4 receptors, which are present on the surface of T-
lymphocytes, monocytes, and macrophages. Because of this affinity, HIV binds to the host target
cell. After binding to the surface of the host cell, the outer membrane of the virus fuses with
membrane of the host cell. At this point, the virus uncoats and unloads the genomic RNA and the
enzyme reverse tran- scriptase (RT). At this point, RT performs three important functions:
1. First, using the RNA as template (positive strand), it catalyses an RNA-dependent DNA
synthesis to produce single-strand DNA (negative strand)
2. Second, using ribonuclease H (section of RT), the enzyme systemically degrades the genomic
RNA strand
3. Third, using the newly synthesised DNA strand as a template, it catalyses a DNA-dependent
DNA synthesis of a complementary copy of DNA. This newly formed DNA double helix is also
called proviral DNA.
The proviral DNA is translocated into the nucleus, where it is integrated into the host genome by
the enzyme integrase. With integration complete, commonly the virus remains latent for a few
months or up to 8-10 years, leaving the person asymptomatic during the entire period. The
presence of host factors or gene products of viruses, like the Epstein-Barr virus, herpes simplex
virus, and cytomegalovirus, can activate the latent virus. This stimulation leads to expression of
the viral genes and the production of viral genomic RNA and messenger RNA (translation),
followed by synthesis of
viral proteins, movement to the surface, and viral budding. At this stage, the protease cleaves the
viral polyproteins. The budding operation kills the host cell in the process, and the newly formed
virus particle becomes matured with the help of glucosidase enzyme and leaks out of the target
cell to once again begin its life cycle. Potential targets for anti-HIV agents The replicative cycle
of HIV comprises a number of steps, which could be considered as adequate targets for
chemotherapeutic intervention. The important targets are viral adsorption, virus-cell fusion,
virion uncoating, reverse transcription (RNA ds DNA) [RT enzyme], proviral DNA integration,
viral transcription (DNA
RNA), viral translation (mRNA Protein), viral budding (assembly/release), and maturation
(protease and glucosidase enzymes). Most of the substances that have been identified as anti-
HIV agents can be allocated to one of the ten classes of HIV inhibitors, according to the stage at
which they interfere with the HIV replicative cycle (Table).
Table
Review of HIV inhibitors according to the stage of intervention in the replicative cycle
1. Adsorption inhibitors
(a) Polysulphates—Dextran sulphate, Curdlan sulphate, Pentosan polysulphate
(b) Polysulphonates—Suramin, Evans blue
(c) Polycarboxylate—Aurin tricarboxylic acid
(d) Glycyrrhizin
2. Fusion inhibitors
Betulinic acid, Mannose-specific plant lectinoylsulphate
3. Virus-uncoating inhibitors Bicyclam derivatives
4. Reverse-transcription inhibitors
(a) Nucleoside derivatives—Zidovudine, Stavudine, Lamivudine—Zalcitabine, Didanosine,
Abacavir
(b) Non-Nucleoside derivatives—Nevirapine, Delavirdine, Efavirenz Loviride, Trovirdine,
Emivirine
5. Integration inhibitors Curcumin, L-chicoric acid
6. DNA-replication inhibitors Antisense constructs
7. Transcription inhibitors
1,4-Benzodiazepine and Fluoroquinolone derivatives
8. Translation inhibitors Ribozymes, Trichosanthin
9. Maturation inhibitors
(a) Protease inhibitors—Saquinavir, Indinavir, Ritonavir, Nelfinavir, Lopinavir, Amprenavir,
Atazanavir, Tipranavir, Darunavir, Amprenavir, Lopinavir
(b) Glucosidase inhibitors—Castanospermine
10. Budding inhibitors Interferon, Hypericin
Reverse Transcriptase Inhibitors
Reverse transcriptase (RT) is a key enzyme that plays an essential and multifunctional role in the
replica- tion of HIV and RT is necessary for the catalytic transformation of single-stranded viral
RNA into the double-stranded DNA, which is integrated into the host cell chromosome.
(a) (b) (c)
RNA---------- ► RNA-DNA--------- ► DNA----------- ► DNA-DNA (single strand) (complex)
(single strand) (double strand)
(a) RNA-dependent DNA polymerase
(b) RNase H activity
(c) DNA-dependent DNA polymerase
Classification
1. Nucleoside analogues
(i) 2’, 3’-dideoxy pyrimidine nucleosides: Zidovudine, Stavudine, Lamivudine, Zalcitabine
(ii) 2’, 3’-dideoxy purine nucleosides: Didanosine, Abacavir
(iii) Acyclic dideoxy purine nucleosides: Adefovir
2. Non-Nucleoside analogues
(i) Dipyridodiazepine: Nevirapine
(ii) Bis heteroaryl piperazines (BHAP): Delavirdine
(iii) Benzoxazinones:Ef avirenz
(iv) a-Anilino phenylacetamide (a-APA): Loviride
(v) Pyridyl ethyl thiourea (PETT): Trovirdine
(vi) Hydroxyethoxy phenyl thymine (HEPT): Emivirine

Nucleoside RT Inhibitors
Mechanism of action: All the dideoxynucleoside analogues are Phosphorylated to the
corresponding mono-, di-, and tri-phosphate by cellular kinases, as illustrated in Fig. 29.3.
Nucleoside triphosphate compete with the substrate for RT enzymes and/or, if incorporated, they
cause chain termination because they do not have the necessary 3’-hydroxyl group, which forms
3’-5’ phosphodiester linkage for further chain elongation. 2’, 3’-dideoxythymidine derivatives.
2’, 3’-dideoxycytidine derivatives
Zalcitabine

2’,3’-dide oxyadenosine derivatives

Didanosine

2’,3-dide oxyguanosidine derivatives

Abacavir
FIGURE Mechanism of action of nucleoside RT inhibitors.

Zidovudine 3'-Azido-2',3'-dideoxythymidine
It is an analogue of thymidine.
Synthesis

Primary alcoholic group of 2’-deoxythymidine is protected as trityl derivative by reaction with

trityl chloride. This is treated with methansulphonyl chloride in pyridine to make the corre-
sponding mesylate. The mesyl group is replaced with an azide group using lithium azide in
dimeth- ylformamaide. Heating this in 55 per cent hydrobromic acid removes the trityl
protection, giving zidovudine.
Zidovudine was the first drug approved for the treatment of AIDS and HIV infection. Jerome
Horwitz of Barbara Ann Karmanos Cancer Institute and Wayne State University School of
Medicine first synthesized AZT in 1964, under a US National Institutes of Health (NIH) grant.
AZT was originally intended to treat cancer.

Stavudine 2’ ,3’-Didehydro-2 ’ ,3’-dideoxy thymidine

Synthesis

The 5’ free hydroxyl group of hydroxybutyrolactone is protected as the silyl derivative. Reaction
of this with lithium and hexamethyl disilazane leads to the enol silyl ether. This is then selenated
using phenylselenyl bromide. Controlled reduction of the lactone carbonyl group with
diisobutylaluminium hydride followed by treatment with acetic anhydride affords acetate
derivative. Glycosidation of uracil with acetate intermediate using trimethylsilyl triflate gives
nucleoside derivative. Oxidation of selenium with hydrogen peroxide leads to transient
selenoxide; this spontaneously splits out phenylselenous acid to form olefin. The silyl protecting
group is then removed by treatment with tetrabutylammonium fluoride to afford stavudine.

Zalcitabine 2,3’-Dideoxy cytidine

Zalcitabine is an analogue of pyrimidine. It is a derivative of the naturally existing
deoxycytidine, made by replacing the hydroxyl group in position 3’ with hydrogen.
2-Deoxycytidine is converted to its bis-methanesulphonate ester by reaction with mesyl chloride.
Reaction of this mesylate with sodium hydroxide leads to the fused oxetane ether. This reaction
consists of hydroly­ sis of the 5’mesylate to an alcohol, followed by backside displacement of the
4’mesylate. Reaction of this oxetane ether with base leads to ring opening and formation of the
double bond. Catalytic hydrogenation affords zalcitabine.
Lamivudine 3’-Thia-2’,3’- dideoxy cytidine

Synthesis starts with the formation of the thioacetal from glyoxal benzoate and the methyl acetal
of thioglyoxal. Reaction of this with 2’-deoxycytidine gives nucleoside derivative. The benzoyl
group is then removed by reaction with base to afford lamivudine.

Didanosine 2 ’, 3 ’-Dideoxy inosine

Didanosine (ddl) is a nucleoside analogue of adenosine. It differs from other nucleoside
analogues because it does not have any of the regular bases; instead, it has hypoxanthine attached
to the sugar ring.
5-Hydroxyl group of 2’-deoxyinosine is protected as benzoyl ester. 3-Hydroxyl group on
reaction with thiocarbonyl diimidazole gives thiocarbamate intermediate, which on heating
undergoes deoxygenation reaction and gives 2’,3’-dideoxyinosine derivative. The benzoyl group
is then removed by reaction with base to afford didanosine.

Abacavir [(17?)-4- [2-Amino-6- (cyclopropylamino) purin-9-yl]-1-cyclopent-2-

enyl] methanol
In this drug, the carbocyclic ring is attached to the base instead of the sugar.

Acylation of phenylalaninol derivative with pentenoic acid ethyl ester gives the imide. This on
treat- ment with triethylamine and the triflate from dibutylboronic acid leads to the transient enol
borate. Aldol condensation of the reactive intermediate with acroelin gives adducts, which is
treated with ruthenium complex. That catalyses an olefin metathesis reaction involving the bis-
terminal diene, which results in cyclization with extrusion of ethylene. Reduction with lithium
borohydride leads to initial formation of a carbinolamine, which cleaves and undergoes further
reduction to give glycol. Acetylation of the diol then gives diacetate. This on reaction with
guanine derivative in presence of palladium leads to coupling, followed by allylic rearrangement
to give acetyl derivative. Saponification affords abacavir.
Adefovir 2-(6-Aminopurin-9-yl)ethoxymethylphosphonic acid

Alkylation of adenine with the side-chain in the presence of base leads to displacement of the
mesyl- ate and formation of Aralkyl derivative. The phosphate esters are then cleaved by
reaction with tri- methylsilyl bromide. Alkylation of the hydroxyl groups with
pivaloyloxymethyl chloride gives adefovir dipivalate.

Non-nucleoside RT Inhibitors (NNRTI)

Mechanism of action: NNRTIs directly interact with the RT at a non-substrate binding site
(allosteric site) and inhibits specifically HIV-1 RT non-competitively. The NNRTI preferentially
inhibits the RNA- dependent DNA polymerization step.
Nevirapine 1-Cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido [3,2-b:2’,3’-e] [ 1,4]
diazepin-6-one
Nevirapine was the first NNRTI approved by the Food and Drug Administration (FDA) of the
United States. It was approved on 21 June 1996 for adults and on 11 September 1998 for
children.
Synthesis
Acylation of 3-ainino-2-chloro-4-methylpyridine with 2-chloronicotinoyl chloride gives
dipyridyl amide derivative. One of the chlorine is displaced with cyclopropyl amino group and
treatment with strong base leads to cyclization and affords nevirapine.
Delavirdine
Synthesis
Alkylation of piperazine with 2-chloro-3-nitropyridine gives mono-substituted piperazine deriva-
tive. Free amino function is protected as t-BOC and reduction of nitro group gives amine, which
on reaction with acetone affords Schiff base, and reduction of this with sodium borohydride
gives isopro- pylamino derivative. t-BOC is deprotected by treatment with trifluoroacetic acid;
free amino group forms amide by reaction with 5-nitroindole-2-carboxylic acid in presence of
DCC. Nitro group is then reduced and reaction with methanesulphonyl chloride gives the
methanesulphonamide derivative delavirdine.
Loviride 2-[(2-Acetyl-5-methylphenyl)amino]-2-(2,6-dichlorophenyl)acetamide
Synthesis

Reaction between 2,6-dichlorobenzaldehyde with sodium cyanide gives cyanohydrin

intermediate, which on reaction with 2-amino-4-methylacetophenone affords aminonitrile.
Controlled hydrolysis of nitrile affords loviride.
Trovirdine N-(5-Bromo-2-pyridyl)-7V-[2-(2-pyridyl)ethyl]thiourea
Synthesis
Reduction of pyridylacetonitrile gives pyridyl-2-ethylamine. This on reaction with 1,1’-thiocar-
bonyldiimidazole gives intermediate thiourea, which on reaction with 2-amino-5-bromopyridine
affords pyridylethyl thiourea derivative trovirdine.
Emivirine 6-Benzyl-l-(ethoxymethyl)-5-isopropyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione
Synthesis

N-Alkylation of bis trimethylsilyl pyrimidine derivative with ethoxy methyl chloride gives 1-
(ethoxymethyl)-5-isopropyl-l,2,3,4-tetrahydro-2,4-pyrimidinedione; this on reaction with benzal-
dehyde in presence of LDA affords 1-(ethoxymethyl)-6-[hydroxy(phenyl) methyl]-5-isopropyl-
l,2,3,4- tetrahydro-2,4-pyrimidinedione. Treatment with acetic anhydride gives acetoxy
derivative, which on hydrohenolysis with palladium-charcoal affords emivirine.
Efavirenz (S)-6-chloro-4- (cyclopropylethynyl)-4- (trifluoromethyl)-lH-benzo [d] [1,3]
oxazin-2 (4H)-one
Synthesis
5-Chloroanthranilic acid is converted to Weinreb amide by reaction with methoxy methylamine;
this followed by trityl protection of the amine moiety gives intermediate. Weinreb amide with
lithium alu- minium hydride followed by addition of trifluoromethyl anion (generated in situ by
the addition of tet- rabutylammonium fluoride to a solution of trifluoromethyltrimethylsilane in
tetrahydrofuran) results in the formation of the secondary alcohols. Manganese dioxide oxidation
of these secondary alcohols to the corresponding amino ketones is followed by treatment with
cyclopropyl lithium acetylides in tetrahydro- furan to provide the tertiary alcohols. Detritylation
using hydrochloric acid in methanol followed by ring closure with phosgene and Hunig’s base
(N,N-diisopropylethylamine) in toluene provide benzoxazinones.

Protease Inhibitors
The HIV protease is encoded by the viral genome and is responsible for the cleavage of the gag-
pol pre- cursor and pol precursor proteins to the mature viral proteins. This proteolytic cleavage
is needed for the maturation and, hence, the infectivity of the virus particles. HIV protease
inhibitors may be expected to suppress virus production and infectivity.
Saquinavir: 7V-[l-Benzyl-2-hydroxy-3-|3-(terr-butylcarbamoyl)-l,2,3,4,4a,5,6,7,8,8a-
decahydroiso-quinolin-2-yl]-propyl]-2-quinolin-2-ylcarbonylamino-butanediamide
Synthesis
Phenylalanine on reaction with formaldehyde and hydrochloric acid undergoes chlormethylation,
which is followed by dehydrochlorination to form tetrahydroisoquinoline derivative. Reduction
with rho- dium-charcoal gives perhydroisoquinoline. Amino function is protected with BOC, and
carboxyl group is activated with DCC and coupled with f-butylamine to give amide.
Hydrogenolysis removes BOC and gives intermediate A.

Amino group of phenylalanine is protected as BOC, and reaction with diazomethane gives diazo-
methyl ketone. Reaction of this with hydrochloric acid gives chloromethyl ketone with the loss
of nitro- gen, and ketone is further reduced to alcohol with sodium borohydride to give
intermediate B.

Intermediate A is alkylated with B. followed by hydrogenolysis to deprotect amine. This reacts

with TV-BOC-protected aspartamate in presence of DCC to give new amide. This on further
hydrogenolysis deprotects amine and reacts with quinoline-2-carboxylic acid in presence of DCC
to afford saquinavir.
Indinavir l-[2-Hydroxy-4- [(2-hydroxy-2,3-dihydro- 1//-inden-1-yl) carbamoyl]-5 -
phenyl-pentyl]-4- (pyridin-3-ylmethyl)- 7V-ter/-butyl-piperazine-2-carboxamide
Synthesis
Step A Preparation of indane moiety

Reaction of l-amino-2-indanol with acetone gives starting cyclic carbinolamine derivative

(indane ace- tonide). Acylation of this acetonide with hydrocinnamyl chloride gives the amide.
Treatment of this amide with lithiohexamethyldisilazane forms anion, where alkylation carried
out with tosyl derivative affords glycidol intermediate A.

Catalytic reduction of pyrazine carboxamide gives the corresponding piperazine. Treatment of

this with BOC-C1 protects selectively at the less steric 4th position. This on reaction with
glycidol intermediate A leads to attack of the free amino group of piperazine on the epoxide,
with consequent ring opening and for- mation of the alcohol. BOC is then removed and
alkylation with 3-chloromethylpyridine affords indinavir.
Ritonavir: l,3-Thiazol-5-ylmethyl [3-hydroxy-5- [3-methyl-2-[methyl- [(2-propan-2-yl-l,3-
thiazol- 4-yl)methyl] carbamoyl] amino-butanoyl] amino-l,6-diphenyl-hexan-2-yl]
aminoformate
Step A

Reaction of phenylalanine with benzyl chloride gives the N,N-bisbenzyl ester. Claisen
condensation of the ester with the anion from acetonitrile leads to displacement of benzyloxide
and thus forms cyanoke- tone. Reaction of this with the benzylmagnesium bromide leads to
addition to the nitrile to form an imine; the imine is reduced and hydrogenolysis leads to
debenzylation and affords diamine intermediate A.
Diamine intermediate A reacts with 4-nitrophenoxyester of the carbonyloxy methyl thiazole,
which leads to net replacement of nitrophenol and formation of the urethane. The second
fragment thiazolylurea-substituted alanine derivative is condensed with free amine of urethane
derivative in presence of DCC to afford ritonavir.
Nelfinavir 2- [2-Hydroxy-3-(3-hydroxy-2-methyl-benzoyl) amino-4-phenylsulphanyl-
butyl| -N-tert- butyl- 1,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxamide
Synthesis

BOC-protected aminobutyrolactone reacts with the anion from thiophenol, and ring opening
takes place to form an acid intermediate; reaction of this with diazomethane leads to
corresponding diazok- etone. This on treatment with hydrogen chloride gives chloro ketone;
ketone is reduced to the alcohol with sodium borohydride. Treatment of this product with
perhydroisoquinoline derivative (saquinavir synthesis A) leads to 7V-alkylation. BOC is
removed by hydrogenolysis, and amidation with 3-hydroxy-2- methylbenzoic acid in presence of
DCC affords nelfinavir.
Nelfinavir acts broadly against cancer tumours, and is currently under investigation for use as an
anti- cancer agent. It inhibits growth and induces apoptosis in prostate cancer and in non-small-
cell lung cancer cell lines in the laboratory, and has similar effects in laboratory mice. It also
induces protein misfolding in the endoplasmic reticulum of cancer cells, and in a small clinical
trial had some success against liposarcoma.
ANTI-HERPES SIMPLEX VIRUS (HSV) AGENTS
Infection with HSV-1 causes diseases of the mouth, face, skin, hands, oesophagus, or brain,
wherea: HSV-2 usually causes infections of the genitals, rectum, skin, hands, or meninges.
29.2.1 Classification of Drugs
1. Pyrimidine nucleoside analogues: Brivudine, Sorivudine, Trifluridine, Fialuridine,
Idoxuridine Netivudine
2. Purinenuc leosides: Vidarabine
3. Acyclic nucleoside analogues: Acyclovir, Ganciclovir, Valaciclovir, Penciclovir, and
Famciclovir
Pyrimidine nucleosides (2-Deoxy thymidine derivatives)

R Ri
• Brivudine —CH=CHBr H
• Sorivudine —CH=CHBr H
• Netivudine —CH=CHCH3 OH
• Idoxuridine 1 OH
• Fialuridine 1 F
• Trifluridine CF3 H
Mechanism of Action:

Brivudine is specifically recognized as a substrate by HSV-1-encoded thymidine kinases, which

convert the compound subsequently to its 5’-mono-, di-, and tri-phosphate. Brivudine
triphosphate can act in a dual fashion with the viral DNA polymerase,
1. as a competitive inhibitor with respect to the natural substrate (dTTP), or
2. as an alternate substrate, which then allows BVDUTP to be incorporated into the DNA chain.
This may, in turn, affect both the stability and functioning of DNA.
Brivudine: (5- [ (E)-2-Bromoethenyl]-1- [ (2R,4S,5R)-4-hydroxy-5- (hydroxymethyl)
oxolan-2-yl]pyrimidine-2,4-dione), and Sorivudine: (5-[(E)-2-Bromoethenyl]-l-
[(2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione)
Reaction between uracil arabinoside and mercuric chloride affords the mercurated derivative.
Palladium- catalysed coupling of this intermediate with ethyl acrylate adds the side-chain.
Saponification of ester gives acid derivative; treatment of this with N-bromosuccinimide results
in a Borodin-like reaction, with the net replacement of the carboxyl group by bromine to afford
sorivudine.
Idoxuridine 5-Iodo-1- (2-deoxyribofuranosyl)pyrimidin-2,4- (1H.3/7)-dione
Synthesis

Iodination of 2’-deoxyuridine affords idoxuridine. It is a nucleoside analogue, a modified form

of deoxy- uridine, similar enough to be incorporated into viral DNA replication, but the iodine
atom added to the uracil component blocks base pairing.

Purine nucleosides
Vidarabine 9-j3-Arabinofuranosyl-6-amino-9-H-purine
It is an adenosine analogue with an altered sugar (arabinose is the 2’-epimer of ribose). It is
active against HSV, poxviruses, rhabdoviruses, hepadenaviruses, and some RNA tumour viruses.
The mechanism of action is similar to brivudine, wherein it inhibits viral DNA polymerase
activity.
It is synthesised from 9-(3’,5’-O-isopropyliden-p-D-xylofuranoside)adenine, which is reacted
with methanesulphonyl chloride to make the mesylate 9-(3’,5’-O-isopropyliden-2’-O-
methansulphonyl- P-D-xylofuranoside)adenine. Prolonged heating in 90 per cent acetic acid
removes the acetonyl protec- tive group from the resulting compound, giving the product.
Reacting this with sodium methoxide leads to the formation of an epoxide 9-(2’,3’-anhydro-P-
luxofuranosyl)adenine. Finally, heating this epoxide with sodium opens the epoxide ring in the
dimethylformamide-water system to make the corresponding dihydroxy derivative, vidarabine.

Acyclic nucleoside analogues

R
Acyclovir —CH2CH2OH
Valaciclovir —CH2CH2OCOCH (NH2)CH(CH3)2
Ganciclovir —CH(CH2OH)2
Penciclovir (instead of OR) —CH2CH2CH (CH2OH)
Mechanism of Action:

The mechanism of action is similar to brivudine. Acyclovir triphosphate acts as a competitive

inhibitor/alternate substrate/chain terminator at the viral DNA polymerase level.
Acyclovir (2-Amino-1,9-dihydro-9- [ (2-hydroxyethoxy) methyl]-6//-purin-6-one), and
Valaciclovir (2-[(2-amino-6-oxo-3,9-dihydropurin-9-yl) methoxy] ethyl-2-amino-3-methyl-
butanoate)
Synthesis

The side-chain is prepared by acylation of dioxolane with acetyl chloride to give the ring-opened
diac- etate derivative. Reaction of this with acetyl guanine in presence of 4-toluenesulphonic acid
leads to open-chain nucleoside derivative. Saponification with base affords acyclovir. Acyclovir
is converted to valaciclovir by reaction with valine in presence of DCC.
Acyclovir is active against most species in the herpesvirus family. In descending order of
activity: herpes simplex virus type I (HSV-1), herpes simplex virus type II (HSV-2), varicella
zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV).
Ganciclovir: 2-Amino-9-(l,3-dihydroxypropan-2-yloxymethyl)-3H-purin-6-one
Synthesis

Epichlorhydrin on reaction with two equivalents of benzyl alcohol anion forms first glycidic
ether; this opens and reacts with second mole of benzyl alcohol to form triol derivative. Reaction
of this with formaldehyde in presence of hydrogen chloride gives chloromethyl ether derivative,
which on reaction with N-acetyl guanine followed by reduction with sodium and liquid ammonia
results in ganciclovir.