Medicinal Chemistry BP601T Notes medichem medi chem

1. Antimycobacterial Agents

2. INTRODUCTION
• The drugs which are used in infections caused by the
bacteria of the genus Mycobacterium, are called as
antimycobacterial agents.
• Mycobacterium are belonging to the Mycobacteriaceae
family, which include the microorganisms responsible
for tuberculosis (caused by Mycobacterium
tuberculosis) and leprosy (caused by Mycobacterium
leprae) as well as a number of other, less common
diseases.
• The mycobacterium are nonmotile, obligate aerobes,
slow growing, acid-fast bacilli (retain red basic fuchsin
dye upon acid wash). The cell wall of mycobacterium is
unique in that it is composed mainly of mycolic acid.

3. TUBERCULOSIS (TB)
• Tuberculosis generally affects the lungs (pulmonary TB), but can also affect
other parts of the body like brain, bones, eyes, skin and kidney
(extrapulmonary TB).
• Most infections do not have symptoms, in which case it is known as latent
tuberculosis. About 10% of latent infections progress to active infection
which, if left untreated, kills about half of those affected.
• The classic symptoms of active TB are a chronic cough with or without
blood, fever, night sweats, fatigability and weight loss.
• M. tuberculosis bacteria are spread through the air when people with
active TB in their lungs cough, spit, speak, or sneeze. So it is airborne
disease.
• Treatment requires the use of multiple antibiotics over a long period of
time as mycobacterium are slow growing. Antibiotic resistance is a
growing problem with increasing rates of multiple drug-resistant
tuberculosis (MDR-TB) and extensively drugresistant tuberculosis (XDR-
TB).

4. i) Multi drug-resistant tuberculosis (MDR-TB)
• MDR-TB is a form of tuberculosis infection
caused by bacteria that are resistant to
treatment with at least two of the most
powerful first-line anti-TB drugs, isoniazid
and rifampicin.
• It can develop when first line anti-TB drugs are
misused or mismanaged.
• MDR-TB takes longer to treat with second-line
drugs (i.e., amikacin, kanamycin, or
capreomycin), which are more expensive and
have more side-effects.

5. ii) Extensively drug-resistant tuberculosis (XDR-
TB)
• XDR-TB is a form of tuberculosis infection
caused by bacteria that are resistant to
treatment with at least one fluoroquinolone
and a second-line injectable drug (amikacin,
capreomycin, or kanamycin).
• It can develop when second-line drugs are also
misused or mismanaged and become
ineffective

6. ANTITUBERCULAR DRUGS
1. First line drugs Isoniazid (Isonicotinic acid
hydrazide, INH)
• It is a synthetic antibacterial agent with
bactericidal activity against replicating, but
bacteriostatic against semidormant and
dormant organisms.

7. Mechanism of action
Isoniazid is a pro-drug and is converted to
reactive species through an oxidation reaction
catalysed by katG enzyme which exhibits
catalase peroxidase activity.

8. • These reactive species
acylate the 4th position
of NADH.

9. • The acylated NADH is no longer capable of
catalysing the reduction of unsaturated fatty
acids, which would be essential for the
synthesis of mycolic acids.
• Thus, isoniazid inhibits the mycolic acid
synthesis, which is important constituent of
mycobacterial cell wall.

10. Pyrazinamide
• It is pyrazine derivative of nicotinamide. • It
causes hepatotoxicity, hyperuricaemia and
possibly acute gouty arthritis.

11. Mechanism of action
• Pyrazinamide is thought to enter into M. tuberculosis
by passive diffusion and is converted into pyrazinoic
acid (its active metabolite) by bacterial
pyrazinamidase enzyme.
• The pyrazinoic acid inhibits mycobacterial fatty acid
synthase-I enzyme and inhibit mycolic acid
biosynthesis.

12. Ethambutol
• It is chemically ethylenediaminodibutanol.
• It is administered as (+)- enantiomer, which is
200- to 500- fold more active than its (–)-
enantiomer

13. Mechanism of action
• Ethambutol inhibits the enzyme
arabinosyltransferase, which is involved in
polymerisation of arabinogalactan (an
essential component of mycobacterial cell
wall).

14. Rifampicin (Rifampin)

15. • It is 4-methylpiperazinyliminomethyl
derivative of natural antibiotic rifamycin.
• Advantage of rifampicin over rifamycin is that
it is orally active.
• It is active against both growing and dormant
bacilli.
• It is also active against M. leprae, Staph.
Aureus, N. meningitidis, H. influenzae,
Brucella, Chlamydia and Legionella.

16. • Mechanism of action
• It inhibits bacterial DNA dependent RNA
polymerase enzyme and thereby inhibits RNA
synthesis.

17. Streptomycin
• It is an aminoglycoside
antibiotic, less
effective than INH or
rifampicin.
• Unlike other first line
drugs, it is
administered
intramuscularly.

18. 2. Second line drugs
• These are the alternative drugs that are useful
in cases of resistance with first line drugs.

19. Ethionamide
• It is rarely tolerated because of intense gastric irritation
and neurological toxicity.
Mechanism of action
• It is a pro-drug and is activated by mycobacterial enzyme
catalase peroxidase to reactive species ethionamide
sulfoxide, which acylates the Cys-243 of inhA protein
(NADH dependent enoyl reductase enzyme) and produce
INH like action.

20. p-amino salicylic acid (PAS)
• PAS is structural analogue of PABA and inhibits
the formation of dihydrofolic acid.

21. Cycloserine
• • It is an antibiotic obtained from Streptomyces
orchidaceus as d-isomer. • It is also active against E.
coli, Staph. aureus, Enterococcus, Nocardia and
Chlamydia.
• Mechanism of action • Mycobacteria are capable of
utilizing naturally occurring L-alanine and converting it
into D-alanine by the enzyme alanine racemase. The D-
alanine is coupled with itself to form D-alanine-D-
alanine complex by the enzyme D-alanine: D-alanine
ligase. This complex is required for peptidoglycan
synthesis in mycobacterial cell wall. • D-cycloserine is
rigid analogue of D-alanine. So it inhibits both of above
enzymes and inhibits peptidoglycan synthesis.

22. Capreomycin

23. • It is a mixture of four cyclic polypeptides, of
which capreomycin Ia and Ib are predominant.
• It is obtained from Streptomyces capreolus.
• As being polypeptide, it is poorly absorbed
from GIT and hence must be given
parenterally.

24. Rifabutin (Mycobutin)

25. • It is structural analogue of rifampicin.
• It shares with rifampicin its common
mechanism of action and common spectrum
of activity against Gram-positive and Gram-
negative bacteria. Hence, there is a complete
cross-resistance between two drugs.
• However, it has better activity than rifampicin
against M. avium complex.

26. Fluoroquinolones
• Ciprofloxacin, ofloxacin, sparfloxacin, levofloxacin
and moxifloxacin inhibit 90-95% of susceptible
strains of M. tuberculosis, M. avium complex and
M. fortuitum.
• They are included in combination regimens
against multidrug resistant tuberculosis and M.
avium complex infection in AIDS patients.
• They are also used in patients where INH,
rifampicin or pyrazinamide are to be avoided due
to side effects

27. Urinary tract anti-
infective agents
• INTRODUCTION
The quinolones are synthetic antibacterial
agents possessing in common an N-1-
alkylated 3-carboxypyrid-4-one ring fused to
another aromatic ring.
• If N-1-alkylated 3-carboxypyrid-4-one ring is
fused with benzene ring, then it is called as
quinolone (quinolin-4-one).

28. MECHANISM OF ACTION
• Quinolones produce bactericidal effect by inhibition of
DNA gyrase and topoisomerase IV enzymes (types of
topoisomerase II). This results in inhibition of DNA
replication and cell division.
• Mammalian cells possess a functionally similar but
structurally different type of topoisomerase II enzyme.
• Quinolones inhibit mammalian topoisomerase II only at
a very high concentration and hence they are least
toxic to the host but selectively toxic to the bacteria.

29. CLASSIFICATION
OF QUINOLONES
I. Earlier agents
The first quinolone derivative to be marketed (in
1965) was nalidixic acid. It was being
commonly used to treat urinary tract
infections caused by Gram-negative aerobes.
As it is highly protein bound (98.5%) in
plasma, its systemic antibacterial effects can
only be achieved at the cost of toxicity.

30. • Later, in 1970s, another quinolone derivatives,
e.g., oxolinic acid and cinoxacin were
launched. But these agents were only
marginally better than nalidixic acid.

31. II. 1 st generation fluoroquinolones
• A major breakthrough was achieved in 1980s with the
introduction of fluoro group to the 6-position of the
quinolone ring results in fluoroquinolones, which have a
broader spectrum of activity and improved pharmacokinetic
properties.
• In 1986, norfloxacin was brought to the market.

32. Other fluoroquinolones were
discovered.

33. IUPAC name of Ciprofloxacin

34. Therapeutic uses of 1st generation
fluoroquinolones
Urinary tract infections
Acute bacterial diarrhoea
Sexually transmitted diseases (gonorrhoea,
trachoma, chancroid)
Bone, soft tissue and wound infections
Respiratory tract infections (bronchitis, sinusitis)
Anthrax (caused by Bacillus anthracis)

35. III. 2 nd generation fluoroquinolones
• Therapeutic uses ✓ Levofloxacin is used in acute bacterial
exacerbation (increase in severity) of chronic bronchitis,
community acquired pneumonia, nosocomical pneumonia,
acute sinusitis, skin and soft tissue infections, UTI and
ophthalmic infections. ✓ Clinafloxacin is used in genital
infections caused by Chlamydia trachomatis.

36. IV. 3 rd generation fluoroquinolones
Therapeutic uses ✓ Gatifloxacin and sparfloxacin are used in
sinusitis, pneumonia and acute bacterial exacerbation of
chronic bronchitis. ✓ Gatifloxacin is used in UTI, gonorrhoea
and skin and soft tissue infections. ✓ Sparfloxacin is used as
an adjuvant in the treatment of tuberculosis, infection due to
Mycobacterium avium complex in AIDS patients, leprosy and
chlamydial genital infections.

37. V. 4 th generation fluoroquinolones
Therapeutic uses ✓ Moxifloxacin is used to treat
community acquired pneumonia, acute
bacterial exacerbation of chronic bronchitis,
sinusitis, skin or soft tissue infections.

38. SAR OF QUINOLONES

39. • The essential structural part for the activity
(pharmacophore) is the 3-carboxypyrid-4-one nucleus.
• The carboxylic acid and the ketone groups are
involved in binding to the DNA-gyrase enzyme. • The
cyclopropyl substitution at N-1 (ciprofloxacin,
clinafloxacin, gatifloxacin, sparfloxacin and
moxifloxacin) extends the spectrum of activity to
include activity against atypical bacteria - Mycoplasma,
Chlamydia and Legionella species. • Substitution at C-2
interferes with the binding of drug with DNA gyrase
enzyme. • Reduction of the 2,3-double bond or the 4-
keto group results in loss of activity. • Introduction of
the fluoro group at C-6 position increasesthe
lipophilicity of the molecule, which in turn improves
the drug penetration through the bacterial cell wall
and also improves the interaction with DNA-gyrase
enzyme.

40. • Heterocyclic substitution at C-7 (piperazine, pyrrolidine)
improves the spectrum of activity especially against
Gram-negative bacteria. • Unfortunately, the
piperazinyl group at C-7 also increases binding to
central nervous system GABA receptors, which
accounts for CNS side effects. • Alkyl substitution on
the piperazine (all fluoroquinolones except norfloxacin
and ciprofloxacin) is reported to decrease the binding
with GABA receptors. • An additional fluoro group at C-
8 further improves drug penetration but also may
increase drug-induced phototoxicity. E.g., lomefloxacin
and sparfloxacin. • Substitution of a methoxy group at
C-8 has been reported to reduce the phototoxicity
(gatifloxacin). • Introduction of a third ring to the
quinolone nucleus gives rise to ofloxacin. Additionally,
ofloxacin has a chiral carbon. The S-(–)-isomer
(levofloxacin) is 2-fold more potent than its racemate
(ofloxacin) and 8- to 128-fold more potent than R-(+)-
isomer.

41. CHELATION OF QUINOLONES
• Quinolones have ability to chelate polyvalent metal ions
(Ca2+, Mg2+, Zn2+, Fe2+ and Al3+), resulting in decreased
solubility and reduced drug absorption. • Chelation occurs
between the metal ion and 3-carboxylic acid and 4-keto group
of quinolones. • Agents containing polyvalent metals should
be administered at least 4 hours before or 2 hours after the
quinolones.

42. Antiviral agents
INTRODUCTION
Virus is an ultramicroscopic infectious agent.
They consist of a core genome of nucleic acid
(either RNA or DNA) contained in a protein
shell (capsid) which in many viruses is also
surrounded by a lipoprotein envelope. The
whole structure (genome + capsid + envelope)
constitutes a virus particle (virion).

44. • A virus is active only when it is within the host
cells. Hence, they are called as obligate
parasites (obligate means entirely dependent
on).
• They not only replicate in host cells but direct
them to make new viral particles.
Therefore, it is very difficult to find an antiviral
drug that would selectively inhibit or kill the
virus without being toxic to the host.

45. Classification of viruses
• They are classified as DNA viruses or RNA
viruses, depending upon the genomic material
in their core.
• Their names and the diseases they produce is
listed below.

49. • Viral Replication a) Replication cycle of DNA viruses• Specific
receptor sites on DNA virus recognize the corresponding surface
proteins on the host cells and get attached (step 1). • The virus
then penetrates the host cell membrane by endocytosis (step
2). • Within the cytoplasm of host cell, capsid of virus is
removed and free genomic material is then entered into host
cell nucleus (step 3). • Inside the host cell nucleus, viral DNA is
transcribed into viral m-RNA by the host cell’s RNA polymerase
(RNAp) enzyme (step 4). • Host cell’s ribosomes then utilise the
viral m-RNA for synthesis of regulatory proteins (step 5). •
Regulatory proteins then initiate the transcription of the early
genes for viral DNA polymerase (DNAp) enzyme, which then
replicate the viral DNA (step 6). • After the viral DNA is
replicated, the late genes are transcribed and translated to
produce structural proteins required for an assembly of new
virions (step 5 and 7). • The release of progeny virus takes place
through budding of the host cells (step 8).

50. • Exception: Poxviruses have their own RNA
polymerase enzyme and replicate in the host
cell cytoplasm to produce viral m-RNA. (This is
like replication of RNA viruses discussed
below.)
• • After the replication of DNA viruses, usually
the host cell is not lysed, but with certain
viruses, the host cells are lysed and damaged.

51. b) Replication cycle of RNA viruses

52. • The attachment (step 1) and endocytosis (step 2) is
same as for DNA viruses. • The M2 proteins of the virus
then allow an influx of H+ into the interior of RNA
viruses which promotes dissociation of genomic RNA
into the cytoplasm of the host cells (step 3). • RNA
viruses have their own RNA polymerase (RNAp) enzyme
to transcribed into m-RNA which then translated into
various proteins (such as viral proteins and RNAp
enzyme). • RNAp enzyme then direct the synthesis of
more viral m-RNA and genomic RNA. • Most RNA
viruses complete their replication in the cytoplasm
without involving host cell nucleus. However, influenza
viruses are transcribed in the host cell nucleus. • The
assembly (step 8) and release of progeny virus (step 9)
are same as of DNA viruses.

53. CLASSIFICATION OF ANTIVIRAL DRUGS
I. Inhibitors of viral penetration and
uncoating

54. Mechanism of action
• Both the drugs inhibit the M2 protein present
on influenza-A virus within the host cells and
thus inhibit H+ mediated dissociation of
genomic RNA into the host cell cytoplasm.
• Uses
✓ They are used orally for prevention and
treatment of influenza-A viral infections.

55. • α –methyl derivative of adamantane produced Rimantidine.
• α–methyl–1–adamantane methylamine is fl umadine.
• 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 and tromantadine possesses
efficacy against clinical Herpes labialis and H. gentalis.
• Replacement of the amino group with OH, SH, CN, or
halogen produced inactive compounds.
• Optical isomers and the racemic mixtures of rimantadine are
equally active.
• Influenza A2 virus, is more susceptible to adamantanespiro–
5–pyrrolidine derivative.

56. Docosanol
• It is 22 carbons alcohol.
• It is effective against lipid enveloped viruses,
such as some HSV, CMV, influenza virus and
paramyxovirus. Mechanism of action
• It inhibits the fusion between the viral
envelope and the host cell plasma membrane.
Uses ✓ In some countries, it is available as
over-the-counter ointment for herpes labialis
(cold sore).

57. II. DNA Polymerase inhibitors

58. a) Purine analogues
• Acyclovir

59. Mechanism of action
• Acyclovir is first converted to acyclovir
monophosphate by viral thymidine kinase
enzyme. It is then further phosphorylated to
di- and triphosphate by host cell enzyme
guanidylate kinase. The resulting acyclovir
triphosphate competes with the viral
deoxyguanosine triphosphate for an access to
the viral DNA polymerase and prevents its
incorporation into DNA synthesis.

60. • Uses ✓ Acyclovir is used orally in the
treatment of HSV-1, HSV-2 and VZV infections.
✓ It is used parentrally in the treatment of
chronic and recurrent HSV and VZV infections
in immunocompromised patients. ✓ It is used
in ointment in the treatment of early genital
herpes and herpes keratoconjunctivitis.

61. Idoxuridine
• It is iodinated derivative of deoxyuridine. • It is converted to
mono, di and triphosphate and inhibits the viral DNA
polymerase. • However, similar incorporation of it into normal
host cell DNA accounts for its toxicity. Uses ✓ It has only
topical ophthalmic use for the treatment of HSV
keratoconjunctivitis.

62. Ganciclovir
• It is hydroxymethyl analogue of acyclovir and so analogue of 2’-
deoxyguanosine. Hence, it has same mechanism of action as
of acyclovir. Uses ✓ It is used parenterally for the treatment of
serious and vision threatening retinitis due to CMV in
immunocompromised patients. ✓ It is also effective for
acyclovir resistant HSV infections. ✓ It is used for prevention
of CMV infection in organ transplant patients.