medicinal chemistry of antiviral drugs by padala varaprasad mainly includes structures, SAR , mechanism of action, uses and toxicity of antiviral drugs

1. UNIVERSITY COLLEGE OF PHARMACEUTIALSCIENCES
K.U. CAMPUS
ANTIVIRAL DRUGS
Presented by
P.VARAPRASAD
HT.No.2004P-1026
M. Pharmacy, I semester,
Department Of Pharmaceutical Chemistry
University College Of Pharmaceutical Sciences

2. CONTETS
1. Introduction to viruses
2. Antiviral drugs
3. Classification
4. Conclusion
5. References

3. INTRODUCTION TO VIRUSES
• Viruses are obligate intracellular parasites.
• Virus can be defined as sub microscopic entity consisting of a single
nucleic acid surrounded by a protein coat and capable of replication only
within the living cells.
• Viruses are much smaller than prokaryotes, ranging in size from about 20–
300 nanometers.
• The infective, extracellular (outside the cell) form of a virus is called the
virion.
• Viruses that infect only bacteria are called bacteriophages and those that
infect fungi are termed mycophages . There are even some viruses called
virophages that infect other viruses.
• The origins of viruses are unclear: some may have evolved from plasmids
while others may have evolved from bacteria.
• Over 5,000 species of viruses have been discovered.
1

4. STRUCTURE OF VIRUS
Capsid - The capsid is the protein shell that encloses
the nucleic acid; with its enclosed nucleic acid, it is
called the nucleocapsid. This shell is composed of
protein organized in subunits known as capsomers.
Envelope - Many types of virus have a glycoprotein
envelope surrounding the nucleocapsid. The envelope
is composed of two lipid layers interspersed with
protein molecules (lipoprotein bilayer) and may contain
material from the membrane of a host cell as well as
that of viral origin.
Nucleic Acid - Just as in cells, the nucleic acid of each
virus encodes the genetic information for the synthesis
of all proteins. While the double-stranded DNA is
responsible for this in prokaryotic and eukaryotic cells,
only a few groups of viruses use DNA. Most viruses
maintain all their genetic information with the single-
stranded RNA.
Fig1.Structure of virus
Fig2. 2

5. TYPES OF VIRUSES
DNA-viruses: Contain mostly double-stranded DNA, a small number single-stranded DNA.DNA
viruses enter the cell nucleus and direct the generation of new viruses. poxviruses, herpes,
adenoviruses papilloma viruses.
RNA-viruses: Contain largely single-stranded RNA (ssRNA).RNA viruses do not enter the cell nucleus
(except the influenza virus).RNA retroviruses uses the viral reverse transcriptase to make a DNA copy
of the viral RNA, which is then integrated into the host genome.
influenza, measles, mumps,meningitis, poliomyelitis, retroviruses (AIDS), arenaviruses.
3

6. THE VIRAL LIFE CYCLE
1. Attachment. The virus recognizes and
binds to a host cell via a receptor
molecule on the cell surface.
2. Entry. The virus or its genetic
material enters the cell.
3. Genome replication and gene
expression. The viral genome is
copied and its genes are expressed to
make viral proteins.
4. Assembly. New viral particles are
assembled from the genome copies
and viral proteins.
5. Release. Completed viral particles exit
the cell and can infect other cells.
Fig4..
4

7. VIRAL ENTRY
Enveloped viruses Non-enveloped viruses
5
Fig5. VIRAL ENTRY

8. VIRUS RECEPTORS
Host cell receptor Virus
CD4 glycoprotein HIV
CCR5, MCP-1, RANTES HIV
chemokine receptor CXCR4 for
cytokine SDF-1
HIV
acetylcholine receptor rabies virus
complement C3d of B
lymphocytes
glandular fever virus
IL-2 receptor on T-lymphocytes T cell leukemia viruses
beta-adrenoreceptor infantile diarrhea viruses
MHC molecules adenoviruses
Table 1. VIRAL RECEPTORS
6

9. Cell-Exit of Enveloped Viruses
7Fig6. Cell-Exit of Enveloped Viruses

10. VIRAL DISEASES
DNA virus
RNA viruses
VIRUS DISEASE
Pox virus Small pox
Herpes virus Chicken pox, Shingles herpes, Glandulan fever
Papilloma virus Warts
Adenovirus Sore throat, Conjunctivitis
Parvo virus Canine distemper
VIRUS DISEASE
Orthomyxovirus Influenza
Paramn virus Measles, mumps, rabies
Picor virus Poliomyelitis
Retrovirus AIDS, T-cell leukaemia
Reo virus Diarrhoea
Arena virus Meningitis, Lassa fever
Bunya virus Encephalitis, haemorrhagic fever
Table 2&3. VIRAL DISEASES
8

11. ANTIVIRAL DRUGS
• Antiviral drugs are a class of medication used for treating
viral infections
• Antiviral drugs do not destroy their target pathogen instead
they inhibit their development.
• In 1963, idoxuridine became the first antiviral compound to
be licensed by the US Food and Drug Administration (FDA)
for the topical treatment of herpes simplex virus (HSV)
keratitis.
• Currently, antiviral therapy is available only for a limited
number of infections.
• Most of the antiviral drugs currently available are used to treat
infections caused by HIV, herpes viruses, hepatitis B and C
viruses, and influenza A and B viruses.
9

12. CLASSIFICATION
1.Antiviral Agents Interfering with Viral Nucleic Acid Replication
(a) DNA polymerase inhibitors
(b) Reverse transcriptase inhibitors
i)Nucleoside reverse transcriptase inhibitors (NRTIs)
ii)Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
2. Antiviral Agents Interfering with Cellular Penetration and Early Replication
(a) Virus uncoating inhibitors
(b)Neuraminidase inhibitors
3.Protease inhibitors
4.Fusion inhibitors
5.CCR5 receptor inhibitors
6.Integrase inhibitors
7.Interferons
10

13. Antiviral Agents Interfering with Viral Nucleic Acid Replication
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HBV, hepatitis B virus; HSV,herpes simplex virus; VZV, varicella-zoster virus.
Table 4. Antiviral Agents Interfering with Viral Nucleic Acid Replication
11
Generic Name Trade Name Spectrum of Activity Dosage Form
Idoxuridine Herplex HSV keratitis 0.1% Solution,
0.5% ointment
Acyclovir Zovirax HSV-1,HSV-2, VZV,EBV 5% Ointment,
injectable (5mg/mL),
capsule (200mg),
tablet(400 and 800mg),
suspension(200 mg/5 mL)
Valacyclovir Valtrex HSV-1, VZV,CMV Tablet (500mg)
Famciclovir Famvir HSV, VZV,EBV,
chronic HBV
Tablet (125,250, and
500mg)
Ganciclovir Cytovene,
Vitrasert
CMV retinitis Injectable (50mg/mL),
capsule (250and 500 mg),
Cidofovir Vistide CMV, HSV-1,HSV-2, VZV,
CMV, EBV
Injectable (75mg/mL)
(a) DNA polymerase inhibitors

14. DNA POLYMERASE INHIBITORS-STRUCTURES
12

15. Acyclovir
Mechanism of action
It is sufficiently similar to the “normal”
nucleosides, so that it can serve as substrate for
the viral DNA polymerases. Since the sugar lacks
the 3’ hydroxyl group it act as chain terminators
13

16. • Acyclovir is prodrug, that can only be converted into the phosphorylated form
by the viral thymidine kinase and hence do not interfere with DNA synthesis
in non-infected cells:
Clinical application
Acyclovir has potent activity against several DNA viruses including HSV-1, the
common cause of labial herpes (cold sore), and HSV-2, the common cause of genital
herpes. Varicella-zoster virus and some isolates of EBV are affected to a lesser extent by
acyclovir .
14

17. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS)
Generic Name Common Name Trade Name Dosage Form
Zidovudine AZT Retrovir Tablet (300 mg),
Capsule(100 mg),
syrup (50 mg/5mL),
injectable (10mg/mL)
Didanosine ddI Videx Tablet (25, 50, 100,
150,and 200 mg)
Stavudine D4T Zerit Capsule (15, 20, 30,
and 40 mg),
powder for oral
solution (1 mg/mL)
Lamivudine 3TC Epivir Tablet (150 mg),
solution(10 mg/mL)
Abacavir ABC Ziagen Tablet (300 mg),
solution(20 mg/mL)
Emtricitabine Emtriva Caplet (200 mg)
Tenofovir Viread Tablet (300 mg)
Table 5. Nucleoside Reverse Transcriptase Inhibitors 15

18. Nucleoside Reverse Transcriptase Inhibitors
16

19. Zidovudine
Mechanism of action
• Intracellularly, zidovudine is phosphorylated to its active 5-triphosphate metabolite,
zidovudine triphosphate (AZT-TP). It acts by competitive inhibition of HIV-1 reverse
transcriptase (RT; the enzyme that HIV uses to make a DNA copy of its RNA)
Deoxythymidine
Zidovudine is a deoxythymidine analog. It is the
first licensed antiretroviral agent. It is the first drug
approved for treatment of HIV
• The RT uses zidovudine
triphosphate instead of thymidine
triphosphate for making DNA, and it
is the zidovudine triphosphate that
interferes with the RT
•Zidovudine can also be incorporated
into the growing viral DNA chain to
cause termination
17

20. Zidovudine
Clinical application
• Zidovudine is used in AIDS and AIDS-related complex (ARC) to control
opportunistic infections by raising absolute CD4 lymphocyte counts.
Side effects
• The most common adverse effect of zidovudine is myelosuppression,
resulting in anemia or neutropenia.
• GI intolerance, headaches, and insomnia may occur but tend to resolve during
therapy.
18

21. Stavudine
• Stavudine is a pyrimidine nucleoside analogue that has significant activity
against HIV-1 after intracellular conversion of the drug to a D4T-triphosphate.
• The first mesylation of thymidine (I) to give dimesylate (II), which is treated with
sodium hydroxide in ethanol to yield oxetane (III). Finally, (III) is converted to
stavudine by means of potassium tert-butoxide in DMSO.
19
stavudine
synthesis

22. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS)
Generic Name Trade Name Dosage Form
Nevirapine Viramune Tablet (200 mg)
Efavirenz Rescriptor Tablet (100 mg)
Delavirdine Sustiva Capsule (50, 100, and200 mg)
Table 6. Non-nucleoside Reverse Transcriptase Inhibitors
20

23. Nevirapine
Clinical application
• Nevirapine and its analogues exhibit antiretroviral effect against azothymidine-
resistant HIV strains
Side effects
• nausea
• loss of appetite
• upper stomach pain
• tiredness
• fever
• unexplained muscle pain
• dark urine
• jaundice
Mechanism of action
Nevirapine is a dipyridodiazepinone derivative that binds
directly to RT. Thus, it blocks RT activities by causing a
disruption of the enzyme's catalytic site. The activity of
nevirapine does not compete with template or nucleoside
triphosphate.
21

24. Antiviral agents interfering with
cellular penetration and early replication
Generic Name Trade Name Spectrum of
Activity
Dosage Form
Amantadine Symmetrel Influenza A Capsule (100mg),
Syrup(50 mg/5mL)
Rimantadine Flumadine Influenza A Capsule (100mg)
Oseltamivir Tamiflu Influenza A and B Capsule (75mg)
Zanamivir Relenza Influenza A and B Inhaled powder
(5mg)
Table 7. Antiviral Agents Interfering with Cellular Penetration and Early Replication
22

25. ANTIVIRAL AGENTS INTERFERING WITH CELLULAR PENETRATION AND EARLY REPLICATION
23

26. ANTIVIRAL AGENTS INTERFERING WITH
CELLULAR PENETRATION AND EARLY REPLICATION
24
Fig7.Antiviral agents interfering with cellular penetration and early replication , acting on influenza

27. Amantadine
• Adamantane derivatives block the migration of protons into the interior of the virions
within endosomes, thereby preventing the pH shift required for uncoating. They act
by blocking the M2 (matrix 2) channel.
structure activity relationship
Amantadine is a adamantane amine
• α –amino derivative of adamantane is amantadine
• N-Alkyl and N,N-dialkyl derivatives of adamantadine exhibit antiviral
activity similar to that of adamantadine HCl.
• Except glycyl derivatives, N–acyl derivatives shows decreased antiviral action
• Replacement of the amino group with OH, SH, CN, or halogen produced inactive
compounds.
Mechanism of action
It inhibits penetration of RNA viral partcles into the
host cell . It also inhibits the early stages of viral
replication by blocking the uncoating of the viral
genome and the transfer of nucleic acid into the host
cell.
25

28. Amantadine
Clinical application
• Amantadine is clinically effective in preventing and treating all type A
strains of influenza, particularly type A2 strains of Asian influenza
virus, and to a lesser extent , German measles (rubella) or atoga virus. It is
also used for parkinsonism
Side effects
• Generally, at therapeutic levels may cause severe CNS symptoms, such as
nervousness, confusion, headache, drowsiness, insomnia, depression,
and hallucinations. The GI side effects include nausea, diarrhea,
constipation, and anorexia. Convulsions and coma occur with high doses
and in patients with cerebral arteriosclerosis and convulsive disorders.
26

29. Neuraminidase Inhibitors(influenza)
• The influenza virus binds to the target cell via interaction of its surface
glycoprotein, haemagglutinin, with the host-cell surface receptor, that
contains sialic acid. Neuraminidase catalytically cleaves glycosidic bonds
between terminal sialic acid residues and adjacent sugars on hemagglutinin.
Allowing the virus to leave the cell once the virus has replicated
• Inhibiting the viral Neuraminidase prevents the virus from leaving the cell
and infecting others.
27
Fig8. Mechanism of Neuraminidase Inhibitors(influenza)

30. Oseltamivir (Tamiflu)
Clinical application
• Oseltamivir is used to treat symptoms caused by the flu virus (influenza). It helps
make the symptoms (such as stuffy nose, cough, sore throat, fever/chills, aches,
tiredness) less severe and shortens the recovery time by 1-2 days.
Side effects
• Nausea
• Vomiting
• Diarrhea
• Dizziness
• Headache
• Nosebleed
• Eye redness
• Sleep problems
• Cough
Mechanism of Action
Oseltamivir inhibits the neuraminidase enzyme,
which is expressed on the viral surface. The enzyme
promotes release of virus from infected cells
28
Fig9. Mechanism of Oseltamivir
(Oseltamivir)

31. PROTEASE INHIBITORS
• Protease cleave the viral polyproteins into individual functional HIV
proteins and enzymes. The various structural components then assemble to
produce a mature HIV virions which is capable of infecting another cell
• Drugs that inhibit HIV protease are designed as transition-state mimetics
that align at the activesite of HIV-1 protease
29
Fig10.Protease inhibitors

32. PROTEASE INHIBITORS
Generic Name Common Name Trade Name Dosage Form
Ritonavir RTV Norvir Capsule (200mg)
Atazanavir ATZ Reyataz Capsule(150and200mg)
Indinavir IDV Crixivan Capsule(200and400mg)
Nelfinavir NFV Viracept Tablet (250 mg),
powder(50mg/g)
Saquinavir Invirase
Fortovase
Capsule (200mg)
Capsule (200mg)
Amprenavir APV Agenerase Capsule(50and150mg)
solution (15mg/mL)
Lopinavir LPV Kaletra Capsule(133.3/33.3mg),
solution (80/20mg/mL)
Table8.Protease Inhibitors
30

33. PROTEASE INHIBITORS
31

34. Saquinavir
Mechanism of action
• It is specifically designed to inhibit HIV protease, thus preventing post translat ional
format ion of viral proteins.
• It contains a hydroxyethylamine moiety rather than the Phe-Pro scissile bond present
in the normal substrate for HIV protease.
Clinical application
• Saquinavir is used in the treatment of advanced HIV infection in selected patients.
Side effects
• GI disturbances,
• Headache
• Rhinitis
• Diarrhea.
Saquinavir was the first PI approved by the U.S.
FDA in December 1995. It is a carboxamide
derivative.
32

35. Fusion inhibitor:Enfuvirtide
enfuvirtide is the first compound of this family to be approved for clinical use.
Enfuvirtide is an oligo peptide consisting of 36 amino acids.
33

36. Enfuvirtide
Mechanism of action
• It is a synthetic peptide that mimics an HR2 fragment of gp41, blocking the
formation of a six-helix bundle structure that is critical in the fusion of the
HIV-1 virion to a CD4-positive T lymphocyte. Specifically, it binds to the
tryptophan-rich region of the gp41 protein.
Clinical application
• Enfuvirtide is used in combination with other antiretrovirals and works
against a variety of HIV-1 variants, but it is not active against HIV-2.
Side effects
• Injection site reactions, including itching, swelling, redness, pain or
discomfort, rash, bruising, hardened skin
• Nerve pain (neuralgia) or numbness, burning, or prickling feeling of your
skin (paresthesia) that lasts up to 6 months.
34

37. CCR5 receptor inhibitor: Maraviroc
Mechanism of action
• Maraviroc selectively binds to the human
chemokine receptor CCR5, which is
present on the cell membrane.
• This binding prevents the interaction of
HIV-1 gp 120 with CCR5-tropic HIV-1
and thereby inhibits the virus from
entering the cell.
35
Fig11.Mechanism of action of maraviroc

38. Maraviroc
Clinical application
• Maraviroc is used with other medications to treat CCR5-tropic HIV type 1.
Side effects
• Maraviroc is generally well tolerated with the incidence of diarrhea, nausea,
headache, and fatigue similar to or less than those of placebo.
• The most common adverse reactions in clinical studies are upper respiratory tract
infection, cough, pyrexia, rash and dizziness.
36

39. Integrase inhibitor:
• Integrase is a viral enzyme that catalyses both 3’ processing of viral DNA
in the cytoplasm, and insertion of the viral DNA into chromosomal DNA
in the nucleus
• Integrase inhibitors (INIs) are a class of antiretroviral drugs designed to
block the action of integrase.
• Since integration is a vital step in retroviral replication, blocking it can halt
further spread of the virus.
nucleus
cell
37
Fig12.mechanism of action of Integrase inhibitor

40. Raltegravir
Mechanism of action
• Raltegravir inhibits the activity of HIV-1 integrase, which impedes the insertion of
HIV-1 DNA into the host cell genome. It inhibits integration at an IC50 of ~10 nM
and the results are consistent with inhibition of the third step of the integration
process (i.e. strand transfer).
Clinical application
• Raltegravir is used along with other medications to treat HIV infection.
Side effects
• pale skin
• stomach pain,
• headache,
• tired feeling,
• dizziness,
• sleep problems (insomnia)
38

41. Interferons
• Interferons belong to the class of cytokines involved in cell-cell signaling,
particularly relating to the early detection of microbialinvasion
• IFNα and IFNβ are produced by most human cells in response to a viral
infection
• Production of interferons is mediated through activation of toll-like receptors
• Its production is transient and requires stimulation by viruses, microbial products
and other inducers
• Their action is mediated through the JAK/STAT and other signaling pathways
• They induce expression of 2,5-oligoadenylate synthase, which in turn produces
oligoadenylate that activates ribonuclease L, resulting in the degradation of
single-stranded RNA, and triggers cellular apoptosis
• IFNs are used to treat hepatitis B and C viral infections
39

42. Conclusion
• Viral infections are a major global health threat. Over the last 50 years, significant
efforts have been devoted to the development of antiviral drugs and great success has
been achieved for some viruses. However, other virus infections, such as epidemic
influenza, still spread globally and new threats continue to arise from emerging and re-
emerging viruses and drug-resistant viruses.
• Even with the most familiar virus targets, there is a continuing need to develop new
drugs or ingenious combinations of drugs that result in greater specificity ( less
toxicity) and increased drug-resistance barriers.
• In the period from 1996 to 2019 we almost halved the number of new HIV infections
and for the millions of people who still live with the virus, ARV treatment enables most
to lead long and healthy lives . A world without HIV is no longer inconceivable.
40

43. References
1. John B. Carter and Venetia A. Saunders. Virology Principles and applications.2013,2,31-48.
2. Arti Kapil, Paniker, Ananthanarayan. Textbook of Microbiology.2013,9,427-570
3. KD Tripathi. Essentials of Medical Pharmacology 2013,7, 798-816
4. James M. Ritter, Flower, Rod,Henderson, Graeme,Loke, Yoon Kong, Macewan, David. Rang
and Dale's Pharmacology. 2016,8,79
5. Williams, David A, and Thomas L. Lemke. Foye's Principles of Medicinal Chemistry.
2002.6,1202–1225.
6. Graham L.Patrick. An Introduction To Medicinal Chemistry.2013,5,468-513
7. V. Alagarsamy Textbook Of Medicinal Chemistry volume ii 2010,399
8. https://en.wikipedia.org/wiki/Antiviral_drug
9. https://bio.libretexts.org/Bookshelves/Microbiology/Book%3A_Microbiology_(Bruslind)/08
%3A_Introdution_to_Viruses
10. https://www.khanacademy.org/science/high-school-biology/hs-human-body-systems/hs-the-
immune-system/a/intro-to-viruses
11. https://www.chemsrc.com/en/cas/144245-52-3_955005.html
12. https://www.researchgate.net/figure/The-HIV-1-life-cycle-and-the-antiretroviral-drug-class-
intervention-points-Entry_fig1_234006451
13. https://www.amboss.com/us/knowledge/Antiviral_agents
14. https://www.drugfuture.com/synth/syndata.aspx?ID=137195
41

44. THANK YOU
Embrace and celebrate the progress
While not letting up the pressure
Until there is a cure.