Anti viral-drug synthesis by Dr Anthony Crasto

SYNTHESIS OOFF AANNTTII--VVIIRRAALL
AAGGEENNTTSS
DR ANTHONY MELVIN CRASTO
Ph.D
2014
PRINCIPAL SCIENTIST
PROCESS RESEARCH

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bbee ddoonnee ffoorr tthhiiss

DDeeddiiccaatteedd ttoo mmyy ssoonn LLiioonneell
CCrraassttoo,,
He was only in first standard in school (dec2007) when
I was Paralysed head to toe.
His smiling face sees me through day in and day out.
Vast readership from academia and industry motivates me, and keeps me going.
I am helping millions with free advertisement free websites and has million hits on
google
Thanks for helping me to keep lionel smiling

AANNTTII--VVIIRRAALL AAGGEENNTTSS
VIRUSES:
Single or double stranded DNA or RNA
enclosed in a protein – CAPSID
Obligate intracellular parasite
Replication depends on synthetic processes of
the host cell
Anti-viral drugs must either block entry or exit
from cell or be active inside the host cell

VVIIRRAALL RREEPPLLIICCAATTIIOONN
 Viral attachment and entry (enfuvirtide, docosanol,
palivizumab)
 Adsorption and penetration into susceptible host
cells (Globulins and interferon-alfa)
 Un-coating of viral nucleic acid (Amantadine)
 Synthesis of early regulatory proteins (Fomivirsen)
 Synthesis of RNA or DNA (RT Inhibitors)
 Synthesis of late regulatory proteins
(Protease Inhibitors)
 Packing and Assembly (maturation) of viral
particles (Rifampicin)
 Release from cells (Neuraminidase Inhibitors)

AANNTTII--VVIIRRAALL AAGGEENNTTSS
Anti-Herpes
Acyclovir Famciclovir Valacyclovir
Ganciclovir Valganciclovir Lamivudine
Vidarabine Idoxuridine Trifluridine
Cidofovir Sorivudine Fomivirsen
Penciclovir

Anti-retroviral Agents
Nucleoside RT inhibitors.
Zidovudine Zalcitabine Didanosine
Stavudine Lamivudine Abacavir
Emtricitabine
Non-nucleoside RT Inhibitors
Nevirapine Delavirdine Efavirenz

AANNTTII--HHeeppaattiittiiss BB
Lamivudine
Adenofovir Dipivoxil
Entecavir
Interferon alfa-2b
Famciclovir
ANTI-Hepatitis C
Pegylated interferon alfa-2a and 2b
Ribavirin, interferon alfa 2a, 2b, alfacon

PPrrootteeaassee IInnhhiibbiittoorrss
Saquinavir Lopinavir/Ritonavir
Indinavir Nelfinavir Amprenavir
Darunavir Atazanavir Tipranavir
Fosamprenavir

AAnnttii--iinnfflluueennzzaa AAggeennttss
Amantadine Rimantadine
Neuraminidase Inhibitors
Oseltamivir (Tamiflu)
Zanamivir
Ribavirin Palivizumab
Interferons

MMiisscceellllaanneeoouuss
Immuno-modulating Agents
Inosiplex Isoprinosine
Foscarnet

AANNTTII--HHEERRPPEESS
AANNTTII--VVAARRIICCEELLLLAA ZZOOSSTTEERR

AACCYYCCLLOOVVIIRR
2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-Purin-
6-one
Acyclovir(9-[2-hydroxy methyl]-9-H-guanine)
 Acyclic guanosine derivative against
HSV1, HSV2, and VZV
 Weaker activity against EBV, CMV
and Human Herpes Virus 6 (HHV 6)

Title: Acyclovir
CAS Registry Number: 59277-89-3
CAS Name: 2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one
Additional Names: acycloguanosine; 9-[(2-hydroxyethoxy)methyl]guanine
Manufacturers' Codes: BW-248U; Wellcome 248U
Trademarks: Acicloftal (Bruschettini); Avirase (Lampugnani); Cycloviran (Sigma-Tau); Maynar (Ferrer); Virmen
(Menarini); Viruseen (Hommel); Zoliparin (Mann); Zovir (GSK); Zovirax (GSK)
Molecular Formula: C8H11N5O3
Molecular Weight: 225.20
Percent Composition: C 42.67%, H 4.92%, N 31.10%, O 21.31%
Literature References: Orally active acyclic nucleoside with inhibitory activity towards several herpes viruses.
Prepn: H. J. Schaeffer, DE 2539963; idem, US 4199574 (1976, 1980 to Wellcome). Convenient synthesis from
guanine: H. Matsumoto et al.,Chem. Pharm. Bull. 36, 1153 (1988). Selectivity of action: G. B. Elion et al., Proc. Natl.
Acad. Sci. USA 74, 5716 (1977). Chemistry, antiviral activity, metabolism: H. J. Schaeffer et al., Nature 272, 583
(1978). In vitro activity: P. Collins, D. J. Bauer, J. Antimicrob. Chemother. 5, 431 (1979). Effect on herpes simplex
infections in mice: H. J. Field et al., Antimicrob. Agents Chemother. 15, 554 (1979); on herpes zoster in
immunocompromised patients: H. H. Balfour et al., N. Engl. J. Med. 308, 1448 (1983). Treatment of primary
episodes of genital herpes simplex infection: Y. J. Bryson et al., ibid. 916; of recurrent genital herpes: S. E. Straus et
al., ibid. 310, 1545 (1984); J. M. Douglas et al., ibid. 1551. HPLC determn in serum and clinical pharmacokinetics: G.
Bahrami et al., J. Chromatogr. B 816, 327 (2005). Symposia on pharmacology and clinical studies: Am. J.
Med. 73, Suppl. 1A, 1-392 (1982); J. Antimicrob. Chemother. 12, Suppl. B, 1-202 (1983); Scand. J. Infect.
Dis. Suppl. 47, 1-176 (1985). Review: R. J. Whitley, J. W. Gnann, Jr., N. Engl. J. Med. 327, 782-789 (1992).
Properties: Crystals from methanol, mp 256.5-257°. LD50 in mice (mg/kg): >10,000 orally; 1000 i.p. (Schaeffer).
Melting point: mp 256.5-257°
Toxicity data: LD50 in mice (mg/kg): >10,000 orally; 1000 i.p. (Schaeffer)
Therap-Cat: Antiviral.
Keywords: Antiviral; Purines/Pyrimidinones.

Structures of guanosine and acyclovir compared

DDeessccrriippttiioonn
The reaction of benzonitrile (I) with refluxing ethylene glycol (II) gives ethylene glycol
monobenzoate (III),
which is chloromethylated with formaldehyde a
and dry HCl in CH2Cl2 affording 1-benzoyloxy-2-chloromethoxyethane (IV). The
condensation of (IV) with 2,6-dichloropurine (V)
by means of triethylamine in DMF yields 2,6-dichloro-9-(2-
benzoyloxyethoxymethyl)purine (VI), which is aminated and
debenzoylated by treatment with
NH3 in methanol at 95 C in a pressure vessel giving 2-chloro-9-(2-
hydroxyethoxymethyl)adenine (VII).
The Sandmeyer reaction of (VII) with N
aNO2 in acetic acid affords 2-chloro-9-(2-hydroxyethoxymethyl)hypoxanthine (VIII),
which is finally amonolyzed with ammonia in methanol at 125 C in a pressure vessel.

TTHHEERRAAPPEEUUTTIICC UUSSEESS
ACUTE HERPES ZOSTER (SHINGLES)
SYSTEMIC ACYCLOVIR PROPHYLAXIS
HSV ENCEPHALITIS ( IV form)
VARICELLA ZOSTER VIRUS INFECTION
CMV PROPHYLAXIS

VVAALLAACCYYCCLLOOVVIIRR
(S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-
methylbutanoate
 L- valyl ester of acyclovir
 Rapidly converted to acyclovir after oral administration
 Serum levels are 3-5x greater than acylcovir
 Treatment of primary and recurrent genital herpes and herpes
zoster infections
 Prevents CMV disease in post-transplant patients

Title: Valacyclovir
CAS Name: L-Valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
Additional Names: L-valine ester with 9-[(2-hydroxyethoxy)methyl]guanine; valaciclovir; ValACV
Literature References: L-Valine ester prodrug of acyclovir, q.v. Prepn: T. A. Krenitsky et al., EP 308065; L. M.
Beauchamp, US4957924 (1989, 1990 both to Wellcome). Evaluation as prodrug: L. M. Beauchamp et al., Antiviral
Chem. Chemother. 3, 157 (1992). Clinical pharmacokinetics: S. Weller et al., Clin. Pharmacol. Ther. 54, 595
(1993). Review of pharmacology and clinical efficacy in herpes virus infections: C. M. Perry, D.
Faulds, Drugs 52, 754-772 (1996). Clinical trial to prevent cytomegalovirus disease in renal transplantation: D.
Lowance et al., N. Engl. J. Med. 340, 1462 (1999); to prevent transmission of genital herpes: L. Corey et
al., ibid. 350, 11 (2004).
Derivative Type: Hydrochloride
Manufacturers' Codes: 256U; BW-256U87; BW-256
Trademarks: Valtrex (GSK)
Properties: Crystalline solid, occurs as hydrate. uv max (water): 252.8 nm (e 8530). Soly in water: 174 mg/ml.
Absorption maximum: uv max (water): 252.8 nm (e 8530)

DDEESSCCRRIPPTTIOONN
Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the
presence of DCC and DMAP to afford the Cbz-protected valyl
ester (III). The N-benzyloxycarbonyl group of (III) was then
removed by either hydrogenation over Pd / C or by transfer
hydrogenation in the presence of formic acid.

FFAAMMCCIICCLLOOVVIIRR
2-[(acetyloxy)methyl]-4-(2-amino-9H-purin-9-yl)butyl acetate
 Diacetyl ester prodrug of 6 deoxy penciclovir and rapidly converted
to PENCICLOVIR by FIRST-PASS metabolism
 Penciclovir does not cause chain termination
 Oral form is approved for managing HSV and VZV infections

Title: Famciclovir
CAS Name: 2-[2-(2-Amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate (ester)
Additional Names: 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine; FCV
Manufacturers' Codes: BRL-42810
Trademarks: Oravir (SKB); Famvir (SKB)
Literature References: Prodrug of penciclovir, q.v. Prepn: M. R. Harnden, R. L. Jarvest, AU 85
47560; eidem, US 5246937 (1986, 1993 both to Beecham); M. R. Harnden et al., J. Med. Chem. 32, 1738 (1989).
HPLC determn in plasma and urine: J. R. McMeekin et al., Anal. Proc. 29, 178 (1992). Review of metabolism and
mode of action: R. A. Vere Hodge, Antiviral Chem. Chemother. 4, 67-84 (1993). Series of articles on pharmacology
and pharmacokinetics: ibid. Suppl. 1, 37-68 (1993). Review of clinical efficacy in herpes zoster and genital herpes: R.
Circelli et al., Antiviral Res. 29, 141-151 (1996).
Properties: White shiny plates from ethyl acetate-hexane, mp 102-104°. uv max (methanol): 222, 244, 309 nm
(e 27500, 4890, 7160). Sol in water (25°): >25% w/v initially; rapidly ppts as sparingly sol monohydrate (2-3% w/v).
Freely sol in acetone, methanol; sparingly sol in ethanol, isopropanol.
Melting point: mp 102-104°
Absorption maximum: uv max (methanol): 222, 244, 309 nm (e 27500, 4890, 7160)

First episode genital herpes
250 mg TID for 5-10 days
Recurrent genital herpes – 250 mg BID for 1 year
Herpes zoster of 3 days – 500 mg TID x 10 days It is as effective as
acyclovir in reducing healing time and zoster associated pain
Famciclovir is a guanine analogue antiviral drug used for the treatment of various herpesvirus
infections, most commonly for herpes zoster (shingles). It is aprodrug form of penciclovir with
improved oral bioavailability.
Famciclovir is marketed under the trade name Famvir (Novartis).
On August 24, 2007, the United States Food and Drug Administration approved the first generic
version of famciclovir.
Generic Famciclovir Tablets (125 mg, 250 mg, 500 mg) are manufactured by
TEVA Pharmaceuticals and Mylan Pharmaceuticals.

DDEESSCCRRIIPPTTIIOONN
Synthesis
This compound has been obtained by two similar ways (Scheme 10704402a): 1)
The reaction of 6-chloropurine-2-amine (I) with 6,6-dimethyl-5 ,7-dioxaspiro [2,5]
octane-4 ,8-dione (II) by means of K2CO3 in DMF gives the expected
condensation product (III), which is methanolized with HCl / methanol yielding 2 -
[2 - (2-amino-6-methoxypurin-9-yl ) ethyl] malonic acid dimethyl ester (IV). The
reduction of (IV) with NaBH4 in t-butanol/methanol affords the corresponding diol
(V), which is finally converted into pecnciclovir by hydrolysis with 2N NaOH. 2)
The reaction of purine (I) with 3-bromopropane-1 ,1,1-tricarboxylic acid triethyl
ester (VI) by means ofK2CO3 in DMF gives the expected condensation product
(VII), which is partially decarboxylated with sodium methoxide in methanol yielding
2 - [2 - (2-amino-6-chloropurin-9-yl) ethyl] malonic acid diethyl ester (VIII). The
reduction of (VIII) with NaBH4 in t-butanol/methanol followed by acetylation with
acetic anhydride affords the corresponding diol diacetate ( IX), which is finally
converted into penciclovir by hydrlysis with 2N HCl. Synthesis of 126242: A
synthesis of famciclovir that corresponds to that previously published and studies
on its oral bioavailability in rats and mice, identifying famciclovir as the preferred
prodrug of BRL-39123 (penciclovir), have been published. (Scheme 12624201a)

Comparable to valacyclovir in treating
zoster and reducing associated pain in
older adults
500 mg TID x 10 days is comparable to
high dose of acyclovir in treating zoster
in immuno-compromised patients and in
opthalmic zoster
Associated with dose-related reductions
in Hepatitis B Virus DNA and
transaminase levels in patients with
chronic HBV hepatitis

PPEENNCCIICCLLOOVVIIRR
2-amino-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6,9-dihydro-3H-purin-
6-one
Penciclovir (9-[4-hydroxy-3-hydroxymethyl but-1-yl] guanine
 An acyclic guanine nucleoside
 Active metabolite of famciclovir
 Spectrum of activity and potency against HSV & VZV is similar
to acyclovir
 Inhibitory activity to HSV

Title: Penciclovir
CAS Name: 2-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)butyl]-6H-purin-6-one
Additional Names: 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine; PCV
Manufacturers' Codes: BRL-39123
Trademarks: Denavir (SKB); Vectavir (SKB)
Literature References: Carba analog of ganciclovir, q.v., active against several herpes viruses. Prepn: U. K. Pandit et
al., Synth. Commun. 2, 345 (1972); R. L. Jarvest, M. R. Harnden, US 5075445 (1991 to Beecham). Synthesis: M. R.
Harnden et al., J. Med. Chem. 30, 1636 (1987); J. Hannah et al., J. Heterocycl. Chem. 26, 1261 (1989). Crystal and
molecular structures: M. R. Harndenet al., Nucleosides Nucleotides 9, 499 (1990). In vitro activity of enantiomers in
comparison with acyclovir, q.v.: G. Abele et al.,Antiviral Chem. Chemother. 2, 163 (1991); against herpes simplex
viruses: A. Weinberg et al., Antimicrob. Agents Chemother. 36,2037 (1992). Clinical pharmacokinetics: S. E. Fowles et
al., Eur. J. Clin. Pharmacol. 43, 513 (1992). HPLC determn in plasma and urine: J. R. McMeekin et al., Anal.
Proc. 29, 178 (1992). Review of development and antiviral activity: M. R. Harnden, Drugs Future14, 347-358 (1989).
Properties: White crystalline solid from water, (monohydrate), mp 275-277°; also reported as colorless matted needles,
mp 272-275°. uv max (in water): 253 nm (e 11500). uv max (aq 0.01N NaOH): 215, 268 nm (e 18140, 10710). Sol in
water (20°): 1.7 mg/ml, pH 7.
Melting point: mp 275-277°; mp 272-275°
Absorption maximum: uv max (in water): 253 nm (e 11500); uv max (aq 0.01N NaOH): 215, 268 nm (e 18140, 10710)
Derivative Type: Sodium salt
Manufacturers' Codes: BRL-39123A
Properties: Occurs as monohydrate, stable crystalline solid. Sol in water (20°): >200 mg/ml. 30 mg/ml soln has pH 11.

PPEENNIICCIICCLLOOVVIIRR
Penciclovir (INN) is a guanine analogue antiviral drug used for the treatment of
various herpesvirus infections.
It is a nucleoside analogue which exhibits low toxicity and good selectivity.
Because penciclovir is absorbed poorly when given orally (by mouth)
it is used more as a topical treatment, and is the active ingredient in the cold
sore medications Denavir (NDC 0135-0315-52), Vectavir and Fenistil.
Famciclovir is a prodrug of penciclovir with improved oral bioavailability.

DDEESSCCRRIIPPTTIIOONN
The synthesis of penciclovir by two related ways has been reported: 1) The reaction of 2 - (hydroxymethyl)
butane-1 ,4-diol (I) with formaldehyde (or an aldehyde such as trimethylacetaldehyde) (II) by means of H2SO4
( or p-toluenesulfonic acid, TsOH) gives the dioxane (III), which by reaction first with methanesulfonyl chloride
and
triethylamine and then with NaI in acetone affords the corresponding 5 - (2-iodoethyl) -1,3-dioxane (IV).
The reaction of (IV) with 2-amino-6-chloropurine (V) by means of K2CO3 in DMF gives the corresponding
condensation product (VI),
which is finally hydrolyzed and deprotected with refluxing 2M aqueous HCl. 2) The reaction of triol (I)
with 2,2-dimethoxypropane (VII) by means of TsOH gives the corresponding
1,3-dioxane (VIII), which by reaction with triphenylphosphine and CBr4 is converted to the 5 - (2-bromoethyl)
derivative (IX) .
The reaction of (IX) with the purine (V) by means of K2CO3 as before affords the corresponding condensation
product (X),
which is hydrolyzed and deprotected with 2M HCl as before.

MMEECCHHAANNIISSMM OOFF AACCTTIIOONN
Inhibitor of viral DNA synthesis
Initially phosphorylated by viral thymidine kinase
Penciclovir triphosphate has a lower
affinity in competitive inhibition of viral DNA
polymerase thus can not cause chain termination
100 fold less potent in inhibiting DNA polymerase
than acyclovir but present in higher concentration
and prolonged period in infected cells

TTRRIIFFLLUURRIIDDIINNEE
Fluorinated pyrimidine nucleoside that
has an in vitro inhibitory activity against
HSV 1 & 2 , CMV, vaccinia and certain
adenoviruses
Inhibits viral DNA synthesis
Phosphorylated intracellularly into its
active form by cellular enzymes
Incorporation into both viral and cellular
DNA prevents its systemic use

Title: Trifluridine
CAS Name: a,a,a-Trifluorothymidine
Additional Names: 2¢-deoxy-5-(trifluoromethyl)uridine; 5-(trifluoromethyl)-2¢-deoxyuridine; F3TDR
Manufacturers' Codes: NSC-75520
Trademarks: TFT Thilo (Alcon-Thilo); Virophta (Dulcis); Viroptic (Burroughs Wellcome)
Molecular Formula: C10H11F3N2O5
Percent Composition: C 40.55%, H 3.74%, F 19.24%, N 9.46%, O 27.01%
Literature References: Prepn: C. Heidelberger et al., J. Am. Chem. Soc. 84, 3597 (1962); eidem, J. Med.
Chem. 7, 1 (1964); C. Heidelberger, US 3201387 (1965 to U.S. Dept. HEW). Crystal structure: A. H.
Tench, Diss. Abstr. Int. B 33, 3587 (1973). NMR study: R. J. Cushley et al., J. Am. Chem. Soc. 90, 709
(1968). Metabolism: D. L. Dexter et al., Cancer Res. 32, 247 (1972); W. J. O'Brien, H. F. Edelhauser, Invest.
Ophthalmol. Visual Sci. 16, 1093 (1977). Pharmacodynamics: B. L. Wigdahl, J. R. Parkhurst,Antimicrob.
Agents Chemother. 14, 470 (1978); G. J. Smith et al., Biochem. Biophys. Res. Commun. 83, 1538 (1978).
Teratogenicity study: M. Itoi et al., Arch. Ophthalmol. 93, 46 (1975). Cytotoxicity and mutagenicity study: E.
Huberman, C. Heidelberger, Mutat. Res. 14, 130 (1972). Clinical studies: H. E. Kaufman, Invest.
Ophthalmol. Visual Sci. 17, 941 (1978); R. A. Hyndiuk et al., Arch. Ophthalmol. 96, 1839 (1978). Review of
mechanism of antiviral activity: C. Heidelberger, Ann. N.Y. Acad. Sci.255, 317 (1975). Review of
pharmacology and therapeutic use: A. A. Carmine et al., Drugs 23, 329-353 (1982).
Properties: Cryst from ethyl acetate, mp 186-189°. uv max (0.1N HCl): 260 nm (e 9960);
(0.1N NaOH): 260 nm (e 6590).
Melting point: mp 186-189°
Absorption maximum: uv max (0.1N HCl): 260 nm (e 9960);
(0.1N NaOH): 260 nm (e 6590)
Therap-Cat: Antiviral (ophthalmic).

Trifluridine monophosphate
irreversibly inhibits thymidylate
synthetase
Trifluridine triphosphate is a
competitive inhibitor of thymidine
triphosphate incorporation into DNA
by DNA polymerases

VVIIDDAARRAABBIINNEE
Adenosine analog with an in vitro activity
against HSV, VZV, and CMV
Phosphorylated intracellularly by host
enzymes to form ara-ATP and then
inhibits viral DNA polymerase
Vidarabine triphosphate is incorporated
into both viral and cellular DNA
Rapidly metabolized in vivo to
hypoxanthine arabinoside through
removal of 6-amino group by adenosine
deaminase – decrease viral activity

Title: Vidarabine
CAS Name: 9-b-D-Arabinofuranosyl-9H-purine-6-amine monohydrate
Additional Names: 9-b-D-arabinofuranosyladenine monohydrate; arabinosyladenine; adenine arabinoside;
spongoadenosine; ara-A
Manufacturers' Codes: CI-673
Trademarks: Arasena-A (Mochida); Vira-A (Warner-Lambert)
Molecular Formula: C10H13N5O4.H2O
Literature References: Purine nucleoside first synthesized as a potential anticancer agent: Lee et al., J. Am. Chem.
Soc. 82,2648 (1960); Reist et al., J. Org. Chem. 27, 3274 (1962); Glaudemans, Fletcher, ibid. 28, 3004 (1963); Reist et
al., ibid. 29, 3725 (1964). Fermentation process using a strain of Streptomyces antibioticus: GB 1159290; J. D.
Howells, A. Ryder, US 3616208(1969, 1971 both to Parke, Davis). Crystal and molecular structure: Bunick, Voet, Acta
Crystallogr. 30B, 1641 (1974). Series of articles on antiviral activity: Antimicrob. Agents Chemother. 1968, 136-179.
Toxicity study: S. M. Kurtz et al., ibid. 180. HPLC determn in plasma and urine: W. P. McCann et al., ibid. 28, 265
(1985). Clinical trial in immunocompromised patients: R. J. Whitley et al., J. Infect. Dis. 165, 450 (1992).
Book: Adenine Arabinoside: An Antiviral Agent, D. Paven-Langston et al., Eds. (Raven Press, New York, 1975) xviii +
425 pp. Review of pharmacology and clinical experience: R. A. Buchanan, F. Hess,Pharmacol. Ther. 8, 143-171
(1980). Comprehensive description: W. Hong et al., Anal. Profiles Drug Subs. 15, 647-672 (1986).
Properties: Crystals from water, mp 257.0-257.5° (0.4 H2O). [a]D27 -5° (c = 0.25). uv max (pH 1): 257.5 nm
(e 12700); pH 7: 259 nm (e 13400); pH 13: 259 nm (e 14000). LD50 in mice (mg/kg): 4677 i.p.; >7950 orally (Kurtz).
Melting point: mp 257.0-257.5° (0.4 H2O)
Optical Rotation: [a]D27 -5° (c = 0.25)
Absorption maximum: uv max (pH 1): 257.5 nm (e 12700); pH 7: 259 nm (e 13400); pH 13: 259 nm (e 14000)
Toxicity data: LD50 in mice (mg/kg): 4677 i.p.; >7950 orally (Kurtz)

TThheerraappeeuuttiicc UUssaaggee
3% ointment – acute
keratoconjunctivitis, superficial
keratitis, recurrent epithelial keratitis
(HSV1 and 2)
IV vidarabine – HSV encephalitis,
neonatal herpes, VZV infection

DDOOCCOOSSAANNOOLL
Saturated 22-carbon aliphatic alcohol.
Inhibits FUSION between plasma
membrane and HSV envelope resulting
in prevention of viral entry into cells and
subsequent viral replication.
Only for orolabial HERPES

GGAANNCCIICCLLOOVVIIRR
(9-[1,3-dihydroxy-2-prepoxymethyl]guanine)
Cyclic guanosine analog that requires
triphosphorylation for activation prior to
inhibiting viral DNA polymerase
Similar structure to acyclovir except in
having additional hydroxymethyl group on
the acyclic side chain

Title: Ganciclovir
CAS Name: 2-Amino-1,9-dihydro-9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one
Additional Names: 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine; 2¢-nor-2¢-deoxyguanosine; DHPG; 2¢NDG
Manufacturers' Codes: BIOLF-62; BW-B759U; BW-759; BW-759U; RS-21592
Literature References: Nucleoside analog structurally related to acyclovir, q.v. Prepn: J. P. Verheyden, J. C.
Martin, US 4355032(1982 to Syntex); K. K. Ogilvie et al., Can. J. Chem. 60, 3005 (1982); W. T. Ashton et
al., Biochem. Biophys. Res. Commun. 108,1716 (1982); J. C. Martin et al., J. Med. Chem. 26, 759 (1983). Antiviral
spectrum in vitro: K. O. Smith et al., Antimicrob. Agents Chemother. 22, 55 (1982). Mode of action study: Y.-C.
Cheng et al., Proc. Natl. Acad. Sci. USA 80, 2767 (1983). Clinical treatment of cytomegalovirus infection in
immunodeficient patients: S. H. Koretz et al., N. Engl. J. Med. 314, 801 (1986). Symposium on pharmacology and
clinical efficacy vs cytomegalovirus: Rev. Infect. Dis. 10, Suppl. 3, S457-S572 (1988). Review:C. S. Crumpacker, N.
Engl. J. Med. 335, 721-729 (1996).
Properties: Crystals from methanol, mp 250° (dec) (Verheyden, Martin); also reported as crystalline monohydrate
from water, mp 248-249° (dec) (Ashton); crystals from water, mp >300° (Martin). uv max (methanol): 254 nm
(e 12880). Soly in water (25°): 4.3 mg/ml at pH 7. LD50 i.p. in mice: 1-2 g/kg (Martin).
Melting point: mp 250° (dec) (Verheyden, Martin); mp 248-249° (dec) (Ashton); mp >300° (Martin)
Absorption maximum: uv max (methanol): 254 nm (e 12880)
Toxicity data: LD50 i.p. in mice: 1-2 g/kg (Martin)
Derivative Type: Sodium salt
Trademarks: Cymevan (Syntex); Cymevene (Syntex); Cytovene (Syntex); Denosine (Syntex); Vitrasert (Chiron)
Molecular Formula: C9H12N5NaO4
Percent Composition: C 38.99%, H 4.36%, N 25.26%, Na 8.29%, O 23.09%

GGaanncciilloovviirr ssyynntthheessiiss

ddeessccrriippttiioonn
The reaction of epichlorohydrin (I) with benzyl alcohol (II) by means of
NaOH in water gives 1,3-di-O-benzylglycerol (III),
which is condensed with paraformaldehyde by means of HCl in methylene
chloride to yield 1,3-di-O-benzyl-2-O-(chloromethyl)glycerol (IV).
Acetylation of (IV) with potassium acetate in acetone affords 1,3-di-O-benzyl-
2-O-(acetoxymethyl)glycerol (V),
which is condensed with diacetylguanine (VI) by means of p-toluenesulfonic
acid in sulfolane giving N2-acetyl-9-[[1,3-bis(benzyloxy)-2-
propoxy]methyl]guanine (VII).
Finally, this compound is deprotected by a treatment with palladium
hydroxide in refluxing cyclohexane.

Monophosphorylated intracellularly by a virus-induced
enzyme
Phosphorylation is catalyzed by a viral thymidine
kinase during HSV, phosphotransferase UL97
encoded gene during CMV infection
Ganciclovir di & triphosphate formed by cellular
enzymes
Triphosphate is a competitive inhibitor of
deoxyguanosine triphosphate incorporation into
DNA inhibiting viral rather than cellular DNA
polymerase
Viral DNA incorporation causes cessation of DNA
chain elongation

VVAALLGGAANNCCIICCLLOOVVIIRR
 L- valyl ester prodrug of ganciclovir
 Hydrolyzed to active compound ganciclovir by intestinal and
hepatic enzymes
 Well absorbed (60%) & rapidly metabolized in intestinal walls &
liver to ganciclovir
 Renal excretion thru GN and TS
Usage:CMV retinitis in AIDS and for prevention of CMV in high risk
kidney, heart transplant.

CCIIDDOOFFOOVVIIRR
(1-[(S)-3-hydroxy-2-(phosphonomethoxy)-
propyl]cytosine dihydrate)
 Cytidine nucleoside analog with inhibitory activity against human
herpes, papilloma, polyoma, pox, and adenoviruses
 Phosphorylation to active disphosphate is independent of viral
enzymes
 After phosphorylation; it acts as potent inhibitor to viral DNA
polymerase

Brodfuehrer, P (1994). "A practical synthesis of (S)-
HPMPC". Tetrahedron Letters 35: 3243. doi:
10.1016/S0040-4039(00)76875-4.

FFOOSSCCAARRNNEETT
Phosphonoformic Acid Inorganic
Pyrophosphate analog that inhibits viral
DNA polymerase, RNA polymerase and HIV
transcriptase directly without requiring
activation by phosphorylation
Taken up slowly by cells and does not
undergo significant intracellular
metabolism
Reversibly blocks the pyrophosphate
binding site of the viral polymerase
Inhibits cleavage of pyrophosphate from
deoxynucleotide triphosphates

SSIIDDEE EEFFFFEECCTTSS
Nephrotoxicity
Symptomatic hypocalcemia
Saline loading may reduce the
risk of nephrotoxicity
Concurrent administration with
pentamidine exacerbates both
nephrotoxicity and hypocalcemia

FFOOMMIIVVIIRRSSEENN
21 mer-phosphorothioate oligonucleotide
First FDA approved anti-sense therapy.
Binding to target mRNA results in
inhibition of immediate early region 2
protein synthesis – inhibiting viral
replication
Injected intravitreally in CMV retinitis in
AIDS

AANNTTIIRREETTRROOVVIIRRAALL
AAGGEENNTTSS

NNUUCCLLEEOOSSIIDDEE RREEVVEERRSSEE
TTRRAANNSSCCRRIIPPTTAASSEE
IINNHHIIBBIITTOORRSS((NNRRTTIIss))
Competitive inhibition of HIV 1 reverse
transcriptase and can be incorporated
into the growing viral DNA chain to
cause termination
Requires intracytoplasmic activation as
a result of phosphorylation by cellular
enzymes to the triphosphate form
Activity against HIV 1, HIV 2
Lactic acidosis & severe hepatomegaly
with steatosis

ZZIIDDOOVVUUDDIINNEE
((AAzziitthhyymmiiddiinnee,, AAZZTT))
Deoxythymidine analog
Decrease rate of clinical disease progression
and prolong survival of HIV infected individuals
Well absorbed from the gut and distributed
to most body tissues & fluids
Eliminated by renal excretion following
glucorinadation in the liver
Combination therapy with other anti-retroviral
agents enhance potency and delay resistance

DDIIDDAANNOOSSIINNEE ((ddddll))
Synthetic analog of deoxyadenosine
Activity is potentiated by hydroxyurea due to
depletion of intraocular pools of d-ATP
Chewable, dispersable tablet, enteric coated
Contains phenylalanine and Na
Should be taken on an empty stomach
Food, fluroquinolones and tetracycline
should be given 2 hrs before didanosine

EEMMTTRRIICCIITTAABBIINNEE
 Formerly called FTC
 Fluorinated analogue of LAMIVUDINE with a long
intracellular half-life(>39 hrs)
 Oral bioavailability: 93%
 CSF level is LOW
 Mean plasma half-line: 8-9 hours
 Renal excretion thru GF and TS
 Contraindicated in children, pregnant women, and patients
with renal and hepatic failure (propylene glycol)
 Most common side effects-HA, diarrhea, hyper-pigmentation
in palms and soles
 Can not combine with LAMIVUDINE

LLAAMMIIVVUUDDIINNEE ((33TTCC))
Cytosine analog ,synergistic with other
antiretroviral nucleoside – Stavudine,
Zidovudine
Oral bioavailability exceeds 80% and it is
not food dependent
Elimination in urine is UNCHANGED
Used in combination therapy
NOTE: no combination with zalcitabine-may
inhibit intracellular phosphorylation of one
another thus decreasing potency.
Approved for the treatment of chronic
Hepatitis B infection

ZZAALLCCIITTAABBIINNEE ((ddddCC))
Cytosine analog with synergistic anti-HIV1
activity with a variety of antiretrovirals
against both zidovudine sensitive and
resistant strains
Associated with dose-dependent peripheral
neuropathy
Oral and esophageal ulcerations
Increase bioavailability in combination with
probenecid or cimetidine
Decrease bioavailability in combination with
antacids and metoclopramide

SSTTAAVVUUDDIINNEE ((dd44TT))
Thymidine analog
High oral bioavailability, not food dependent
Renal excretion thru GF and TS
Major dose-limiting toxicity:
Dose-related peripheral sensory neuropathy
Pancreatitis, arthralgias, elevation of serum
aminotransferases
Phosphorylation is reduced by zidovudine

AABBAACCAAVVIIRR
Guanosine analog
Well absorbed during oral administration
Metabolized by alcohol dehydrogenase
and glucuronosyl-transferase to inactive
metabolites
Fatal hypersensitivity reactions
Nausea, vomiting, diarrhea, headache,
fatigue
Hyperglycemia, hypertriglyceridemia and
lactic acidosis

NNUUCCLLEEOOTTIIDDEE IINNHHIIBBIITTOORR

TTEENNOOFFOOVVIIRR
Acyclic nucleoside phosphonate
competitively inhibits HIV reverse
transcriptase and cause chain
termination after incorporation to DNA
Indicated for use in combination with
other antiretroviral agents

NNEEVVIIRRAAPPIINNEE
Oral bioavailability is > 90%
Not food dependent
Used as a component of a combination
antiretroviral regimen
Effective in the prevention of transmission
of HIV from mother to newborn
Causes severe life threatening rashes

DDEELLAAVVIIRRDDIINNEE
Oral bioavailability of about 85 %
Metabolized to inactive metabolites by the
CYP3A & CYP2D6 P450 enzymes
Plasma concentrations are reduced by
antacids, didanosine, phenytoin,
phenobarbital, carbamazepine, rifabutin,
rifampin, nelfinavir & saquinavir
Concentrations increased by
clarithromycin, fluoxetine, & ketoconazole

EEFFAAVVIIRREENNZZ
Principally metabolized by CYP3A4 & CYP2B6
to inactive hydroxylated metabolites
Principal adverse effects: CNS (dizziness,
drowsiness, insomnia, headache, confusion,
amnesia, agitation, delusions, depression,
nightmares, euphoria)
Pyschiatric symptoms
rashes

PPRROOTTEEAASSEE IINNHHIIBBIITTOORRSS
Protease--responsible for cleaving
precursor molecules (immature budding
particles)
PI---result in the production of immature,
non-infectious viral particles
Associated w/ spontaneous bleeding in
hemophilia A & B
Do not undergo process of phosphorylation

SSAAQQUUIINNAAVVIIRR
Saquinavir H- hard gel capsule – poor
bioavailability, should be taken within 2 hrs
after a fatty meal
Saquinavir S – soft gel capsule – improved
absorption 3x than hard gel capsule
Subject to first pass-metabolism by CYP3A4
Levels are increased by ritonavir, nelfinavir,
delavirdine, indinavir, ketoconazole,
clarithromycin, & grapefruit juice

RRIITTOONNAAVVIIRR
An inhibitor of HIV 1 & HIV 2 proteases
High bioavailability that is increased
with food
Common adverse effects: GIT
disturbances, paresthesias, increase
aminotransferase level, altered taste,
hypertriglyceridemia

IINNDDIINNAAVVIIRR
Specific inhibitor of HIV- 1 & HIV-2 proteases
Higher CSF penetration
Must be consumed in empty stomach for
maximal absorption
Most common adverse effects are indirect
hyperbilirubinemia & nephrolithiasis due to
crystalization

NNEELLFFIINNAAVVIIRR
Higher absorption in the fed state
Common adverse effects: diarrhea &
flatulence

AAMMPPRREENNAAVVIIRR
Rapidly absorbed from the GIT and
can be taken with or without food
High fat meals decrease absorption
Common adverse effects: nausea, vomiting,
diarrhea, peri-oral paresthesias, rash
Steven Johnson’s syndrome
Inhibits CYP3A4 activity

FFUUSSIIOONN IINNHHIIBBIITTOORR

EENNFFUUVVIIRRTTIIDDEE ((TT--2200))
Newly approved antiretroviral agent
Blocks entry into the cell
A synthetic 36-amino acid peptide binds
to the gp41 subunit of the viral envelope
glycoprotein thus preventing the
conformational changes required for the
fusion of the viral and cellular
membranes
Administered subcutaneously in
combination with other retroviral agents

ANTI-HHEEPPAATTIITTIISS AAGGEENNTTSS

AADDEEFFOOVVIIRR
Phosphorylated by cellular kinases
to the active diphosphate metabolite
Competitively inhibits HBV DNA
polymerase
Chain termination after incorporation
into viral replication

EENNTTEECCAAVVIIRR
Oral guanosine nucleoside analog
Competitively inhibits all 3 functions of HBV
DNA polymerase—base priming, reverse
transcription of negative strand and synthesis
of positive strand of HBV DNA.
Taken by empty stomach half life 15 hours
Significantly HIGHER rates of HBV DNA
viral suppression than lamivudine.

IINNTTEERRFFEERROONN AALLFFAA
Endogenous proteins that exert complex
antiviral immunomodulatory & antiproliferative
activities through cellular metabolic process
Enzyme induction, suppression of cell
proliferation, immunomodulatory activities &
inhibition of viral replication
Inhibition of viral penetration & uncoating
Treatment of both HBV & HCV

IINNTTEERRFFEERROONN AALLPPHHAA 22aa
Approved for the treatment of chronic
Hepatitis C, AIDS associated Kaposi’s
sarcoma, hairy cell leukemia,
chronic myelogenous leukemia

IINNTTEERRFFEERROONN AALLPPHHAA 22bb
Only preparation licensed for treatment of
HBV & acute HCV
Leads to loss of HbeAg, normalization of
aminotransferases
Administered subcutaneously or
intramuscularly
Hairy cell leukemia, malignant melanoma,
follicular non-Hodgkin’s lymphoma, AIDS
related kaposi’s sarcoma, & chronic
Hepatitis C

PPEEGGYYLLAATTEEDD IINNTTEERRFFEERROONN AALLFFAA
Recently introduced for treatment of
chronic hepatitis C
Longer duration with slower
clearance

RRIIBBAAVVIIRRIINN
Guanosine analog that is phosphorylated
intracellularly by host cell enzymes
Interferes w/ the synthesis of guanosine
triphosphate
Inhibit capping of viral messenger RNA
Inhibit viral RNA dependent RNA polymerase of
certain viruses
Influenza A, parainfluenza, RSV, paramyxoviruses,
HCV & HIV 1

ANTI-IINNFFLLUUEENNZZAA AAGGEENNTTSS

AMANTADINE/RRIIMMAANNTTAADDIINNEE
(1-aminoadamantane hydrochloride)
a-methyl derivative - rimantadine
Inhibits uncoating of viral RNA influenza A
within infected cell thus preventing
replication
Effectively reduce the duration of
symptoms of influenza when administered
within 48 hrs of onset
Primary target is M2 proteins

OSELTAMIVIR/ZZaannaammiivviirr
Neuroaminidase inhibitors
Inhibits replication of
both influenza A & B
5 day course regimen for
both influenza A & B
NOTE: Treatment for Bird Flu

PPAALLIIVVIIZZUUMMAABB
Prevention of RSV in high risk
infants—premature and those with
broncho dysplasia and congenital
heart disease.
Humanized monoclonal antibody
IMQUIMOD
•Immune response modifier effective
in topical treatment of external
genitalia & perianal warts

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TTHHAANNKK YYOOUU!!
DR ANTHONY CRASTO
amcrasto@gmail.com
http://newdrugapprovals.org/

Anti viral-drug synthesis by Dr Anthony Crasto

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