2. Unit II
• Macrolide: Erythromycin Clarithromycin, Azithromycin.
Miscellaneous: Chloramphenicol*, Clindamycin.
• Prodrugs: Basic concepts and application of prodrugs
design.
• Antimalarials: Etiology of malaria. Quinolines: SAR,
Quinine sulphate, Chloroquine*, Amodiaquine,
Primaquine phosphate, Pamaquine*, Quinacrine
hydrochloride, Mefloquine.
• Biguanides and dihydro triazines: Cycloguanil pamoate,
Proguanil.
• Miscellaneous: Pyrimethamine, Artesunete,
Artemether, Atovoquone.

3. Macrolide: Erythromycin
Clarithromycin, Azithromycin.
• Macrolides are bacteriostatic agents.
• Erythromycin —a metabolite isolated in 1952
from the soil microorganism Streptomyces
erythreus found in the Philippines, and one of
the safest antibiotics in clinical use.

5. • Chemistry: They are characterized by five common
chemical features.
1. A macrocyclic lactone usually has 12–17 atoms, hence the
name macrolide.
2. A ketone group.
3. One or two amino sugars glycosidically linked to the
nucleus.
4. A neutral sugar linked either to amine sugar or to nucleus.
5. The presence of dimethyl amino moiety on the sugar
residue, which explains the basicity of these compounds,
and consequently the formation of salts.
6. The antibacterial spectrum of activity of the more potent
macrolides resembles that of penicillin.
7. Examples: erythromycin, oleandomycin, clarithromycin,
flurithromycin, dirithomycin, azithromycin.

6. MOA
• Erythromycin acts by binding to the 50S
subunit of bacterial ribosomes to inhibit
translocation, but other mechanisms of action
also appear likely. Because erythromycin and
chloramphenicol bind to the same egion of
the ribosome, they should not be
administered together as they will compete
with each other and be less eff ective.

7. • Azithromycin
contains a 15-
membered
macrocycle
where an N -
methyl group has
been
incorporated into
the macrocycle. It
is one of the
world’s best-
selling drugs.

8. • Properties and uses:
• Azithromycin is a white powder, practically
insoluble in water, soluble in anhydrous
ethanol and methylene chloride.
• It is very stable under acidic conditions, is less
active against Streptococci and Staphylococci
than erythromycin, and is far more active
against respiratory infections due to H.
influenzae and Chlamydia trachomatis

9. Miscellaneous: Chloramphenicol*,
Clindamycin.
• MECHANISM OF ACTION
• Chloramphenicol binds to the 50S subunit of
rRNA and prevent the transpeptidation
process (peptide chain on tRNA at P site is
transferred to tRNA at A site and peptide bond
is formed). Thus it inhibits bacterial protein
synthesis.
• It is bacteriostatic to most pathogens but is
bactericidal to H. influenzae.

10. • Chloramphenicol (chloromycetin) is a broad
spectrum antibiotic.
• It was originally produced by fermentation of
from the strain Streptomyces venezuelae, but
its comparatively simple chemical structure
soon resulted in several efficient total
chemical syntheses.

11. • With two chiral centers, it has four
stereoisomers. Out of which, only isomer with
configuration (1R, 2R) is significantly active.
• Chloramphenicol drug is intensively bitter in
taste and poor water soluble. To overcome
this limitations, there are two pro-drug forms
of chloramphenicol are available.
• The bitter taste is masked for use as paediatric
oral suspension by forming its palmitate ester,
which is cleaved in the duodenum to liberate
the drug.

12. Its poor water solubility is largely overcome by
forming sodium salt of its hemisuccinate ester
(chloramphenicol sodium succinate).

14. • THERAPEUTIC USES
• Because of the propensity to induce bone
marrow depression (failure to produce blood
cells) and aplasia (failure of an organ or tissue to
develop or to function normally), the use of
chloramphenicol is no longer justified in treating
minor infections.
• It is widely used topically for treating
conjunctivitis and external ear infections.
• It is used as an alternative to tetracyclines for
rickettsial, chlamydial infections, cholera and
brucellosis.

15. Clindamycin

16. • Properties and uses:
The antibiotic Clindamycin is obtained from Actinomycetes, Streptomyces,
and Lincolnensis.
The ability of Clindamycin to penetrate into bones, adds to its qualities and it
gets promoted in the chemotherapy of bone and joint infections by
penicillin resistant strains of S. aureus.
Variation of the substituents on pyrrolidine portion and C-5 side chain affects
the activity.
Some of the examples are as follows:
i. N-demethylation imparts activity against gram-negative bacteria.
ii. Increase in the chain length of the propyl substitutent at C-4 position in
pyrrolidine moiety up to n-hexyl increase in vivo activity.
iii. The thiomethyl ether of α-thiolincosamide moiety is essential for
activity.
iv. Structural modifications at C-7 position, such as introduction of 7S
chloro or 7R-OCH3, change the physiochemical parameters of the drug
(i.e. partition coeffi cient), and thus, alter the activity spectrum and
pharmacokinetic properties. The usual side effects include skin rashes,
nausea, vomiting, and diarrhoea.

17. Prodrug
INTRODUCTION
Almost all drugs possess some undesirable
physicochemical and biological properties. Their
therapeutic efficacy can be improved by minimizing or
eliminating the undesirable properties while retaining
the desirable ones. This can be achieved through,
✓ The biological approach (alter the route of
administration)
✓ The physical approach (modify the design of the
dosage form)
✓ The chemical approach (design and development of
new drugs - prodrugs)

18. What is prodrug?
• A prodrug is a chemically modified inert
(biologically inactive) drug precursor which is
biotransformed in a predictable manner to
liberate pharmacologically active parent
compound.
• A prodrug is also called as pro-agent,
bioreversible derivative or latentiated drug.
So, the design of prodrug is also called as drug
latentiation.

19. Concept of prodrug
• Depending upon the constitution, lipophilicity,
method of bioactivation and the catalyst
involved in bioactivation, prodrugs are
classified into two categories: carrier-linked
prodrugs and bioprecursors.

20. a) Carrier-linked prodrugs are the ones where
the active drug is covalently linked to an inert
carrier. They are generally esters or amides.
Thus, the active drug is released by hydrolysis,
either chemically or enzymatically. Such
prodrugs have increased lipophilicity due to
attached carrier.

21. • There are instances where the prodrug
comprises of two pharmacologically active
agents coupled together to form a single
molecule such that each acts as the carrier for
the other. Such prodrugs are called as mutual
prodrugs. For example, benorylate is a mutual
prodrug of aspirin and paracetamol.

22. b) Bioprecursors are obtained by chemical modification
of the active drug but do not contain a carrier. Such
prodrugs have almost the same lipophilicity as the
parent drug and are generally bioactivated by
oxidation or reduction reaction.

23. APPLICATIONS OF PRODRUG DESIGN
1. Improvement of taste
• This is an important in case of pediatric dosage
form to overcome the bad taste of drugs.
This can be achieved either by decreasing
drug solubility in saliva or by lowering the
affinity of drug towards taste receptors.
• Examples of drugs with improved taste are
chloramphenicol palmitate and clindamycin
palmitate.

25. 2. Improvement of odour
• The antileprotic drug ethyl mercaptan is a foul
smelling liquid of boiling point 35 ⁰C. It is
converted into its phthalate ester which has
higher boiling point and is odourless.

26. 3. Change of physical form of drug • Some drugs which are in
liquid form, are unsuitable for formulation as a tablet. These
are converted to solid prodrugs by forming symmetrical
molecules having a higher tendency to crystallize. For
example, esters of ethyl mercaptan and trichloroethanol.

27. 4. Reduction of GI irritation • The NSAIDs, especially the
salicylates, have a tendency to lower the gastric pH and
induce or aggravate ulceration. • Examples of prodrugs
designed to overcome GI irritation are as follow.
➢ Salsalate or Aspirin prodrug of salicylic acid

28. ➢ Isonicotinic acid hydrazide prodrug
of isonicotinic acid

29. ➢ Fosfestrol prodrug of
diethylstilbestrol

30. 5. Reduction of pain on injection • Intramuscular injections are
particularly painful when the drug precipitates into the
surrounding cells. • For example, fosphenytoin is the water
soluble disodium phosphate ester prodrug of phenytoin that
was developed to overcome the solubility problem of
phenytoin during parenteral administration.

31. 6. Enhancement of solubility and dissolution rate of drug • This is
desired for orally given drugs or drugs in parenteral or
ophthalmic formulation. • In order to enhance water
solubility, an acidic carrier can be attached to the drugs with
hydroxyl functional group to form half-esters. The other half
of carrier can form sodium, potassium or amine salts and
make the prodrug water soluble.

32. For example, succinic acid is attached with chloramphenicol to
form chloramphenicol hemisuccinate (half-ester). The later is
then forms chloramphenicol sodium succinate which is water
soluble prodrug of chloramphenicol.

33. 7. Enhancement of chemical stability
• Carbenicillin cannot be given orally because of instability in
gastric acid. Its ester prodrugs – carfecillin and carindacillin
are stable at gastric pH.

34. 8. Enhancement of bioavailability (lipophilicity) •
Lipophilicity of drugs is required for better
absorption. • The intraocular penetration of
polar drugs such as β-blockers and
epinephrine, in the treatment of glaucoma,
can be improved by use of lipophilic carrier
prodrugs. • For example, ✓ Nadolol diacetate
(diacetyl ester prodrug) is 20 times more
lipophilic and 10 times more readily absorbed
ocularly as compared to nadolol.

36. 9. Prevention of presystemic metabolism •
Several corticosteroids undergo extensive
first-pass metabolism which can be prevented
by use of their ester or ether prodrugs. E.g.,
triamcinolone acetonide.

37. 10. Prolongation of duration of action
• This is desired for the drugs having short duration of
action to minimize the frequency of dosing.
• This can be achieved by either controlling the release of
prodrug into the blood or controlling the bioactivation
of it.
✓ Examples of controlling the release of prodrug into the
blood: Intramuscular depot injections of lipophilic ester
prodrugs of steroids (testosterone cypionate and
propionate, estradiol propionate) and antipsychotics
(fluphenazine enanthate and decanoate).
✓ Examples of controlling the bioactivation of prodrug:
Ophthalmic solution of diester prodrug of pilocarpine
in treatment of glaucoma.

39. INTRODUCTION
• Malaria is caused by protozoa type of parasites.
• It is transmitted or spread through infected
female mosquito – Anopheles.
• The specific protozoa causing malaria are from
the genus Plasmodium.
• Only four out of approximately 100 species cause
malaria in human. These are – Plasmodium
falciparum, P. malariae, P. vivax and P. ovale.
• Drugs used in malaria are known as antimalarial
agents or antiprotozoal drugs which are from the
class antiparasitic agents.

40. Etiology

42. ✓ It strarts with the bite of an infected female mosquito to
human.
✓ The parasites (protozoa) in the form of sporozoites enter into
the blood stream of humans and then reach to the liver.
✓ In the liver, sporozoites grow and multiply as trophozoites (1, 2
and 3) and make schizontes (4).
✓ These schizontes are then liberated from liver in the form of
merozoites.
✓ These merozoites then enter into the RBCs, where they grow
and multiply as trophozoites (5, 6, 7 and 8) and make
schizontes (9).
✓ The infected RBCs rupture and merozoites are liberated (10).
✓ Some merozoites developed into male and female sexual
forms – gametocytes (11 and 12).
✓ These gametocytes then can be acquired by the female
mosquito after biting the infected human.

43. ✓ Gametocytes mature in female mosquito’s stomach to
form zygotes, which grow to form oocysts.
✓ From this oocysts, sporozoites are developed, which
are released into the body cavity of female mosquito
and migrat to salivary gland of mosquito.
✓ Upon biting of this infected mosquito to another
human body, these sporozoites are transmitted from
saliva of mosquito to human body.
• In this way, malarial parasites complete their asexual
cycle in human body and sexual cycle in mosquito
body.
• In case of P. vivax and P. ovale, some parasites may lie in
dormant stage in liver and form hypnozoites. These
hypnozoites may be liberated at periodic intervals and
relapse may occur.

44. STRUCTURE–ACTIVITY
RELATIONSHIP
• The substitution of a hydroxyl group on one of the ethyl
groups on the tertiary amine (hydroxy quinoline),
reduces toxicity.
• Incorporation of an aromatic ring in the side chain (e.g.
amodiaquine) gives a compound with reduced toxicity
and activity.
• The tertiary amine in the side chain is important.
• The introduction of an unsaturated bond in the side
chain was not detrimental to activity.
• The 7-chloro group in the quinoline nucleus is optimal,
the methyl group in position 3 reduces activity, and an
additional methyl group in position 8 abolishes activity.
• The D-isomer of chloroquine is less toxic than its L-
isomer.

45. ANTIMALARIAL DRUGS
• Quinine was the first known antimalarial agent. It is a
quinoline-4-methanol derivative possessing a
substituted quinuclidine ring.
• Quinine is an alkaloid obtained from cinchona bark
and has been used in the treatment and prevention
of malaria since 1820.

46. • A second drug that played a role in the
development of synthetic antimalarial drugs was
9- aminoacridine.
• It was known to exhibit antibacterial activity.
Whereas, a derivative of it – quinacrine
synthesized in 1934, was found to possess weak
antimalarial activity.

47. • With the beginning of World War II and an
interruption in the supply of Cinchona bark
from East Indies, an effort was begun to
search for synthetic alternative to quinine and
more effective antimalarial agents than
quinacrine.

48. • 4-substituted quinolines
• This class includes 4-aminoquinolines and
quinolone-4-methanols.

49. • These two drugs have structural similarities
with right half structure of quinacrine.
• Chloroquine is the most effective antimalarial
agent of the hundreds of 4- aminoquinolines
synthesized and tested during World War II.
• The introduction of hydroxyl group to N-ethyl
group results in hydroxychloroquine.

50. Mechanism of action of chloroquine
• Chloroquine has a preferential accumulation
in parasitized erythrocytes. Its accumulation in
parasites’ food vacuoles inhibits the enzyme
heme polymerase and thus inhibits the
polymerisation of free heme to hemozoin
(which is nontoxic to parasites). Thus, there is
accumulation of free heme, which is toxic to
the parasites.

51. IUPAC name of chloroquine

52. • Uses of chloroquine
✓ It is blood schizonticidal in all types of
malarial parasites but gametocidal only in P.
vivax and P. ovale. Resistance to chloroquine
among the strains of P. falciparum is most
common.
✓ It is used for chemoprophylaxis, where P.
falciparum malaria is not resistant to
chloroquine.

53. • Quinoline-4-methanol Mefloquine
• It is potent blood schizonticide against P.
falciparum, P. vivax and P. ovale.

54. • It is phenanthrene methanol derivative and
structurally similar to mefloquine. • It has
potent blood schizonticidal action against all
four malarial parasites.

55. • It is newer drug with structural similarities to
mefloquine and halofantrine.
• It is used in combination with artemether
against multidrug resistant P. falciparum
malaria.

57. • These two drugs have structural similarities with
left half structure of quinacrine.
• Pamaquine was the first agent from this class to
be introduced for treatment of malaria in 1926,
but now it has been replaced by primaquine.
• Primaquine possess schizonticidal activity in
exoerythrocytic stage (hypnozoites) and
gametocidal activity against all forms of malarial
parasites. It is not active against erythrocytic
state of parasites. So, it is the drug of choice for
the treatment of relapsing P. vivax and P. ovale
forms of malaria

58. • IUPAC name of pamaquine

59. • Biguanide and dihydrotriazines
• Proguanil is a biguanide pro-drug and is
activated after metabolism into cycloguanil
which is dihydrotriazine derivative.

61. • Mechanism of action of Cycloguanil:
• It is structural analogue of pteridine portion of dihydrofolic
acid. So, it blocks the reduction of dihydrofolic acid into
tetrahydrofolic acid by competitively inhibiting the enzyme
dihydrofolate reductase.

62. • Use:
• It is used in combination with atovaquone as
chemoprophylaxis for P. falciparum malaria as
well as for the treatment of chloroquine
resistant P. vivax and multidrug resistant P.
falciparum malaria.

63. • Artemisinin is obtained from a Chinese herb
Artemisia annua. • Artesunate, artemether
and arteether are semi-synthetic derivatives
of artemisinin.

64. Mechanism of action
• Initially, the ferrous protoporphyrin-IV enzyme
(present in parasitic food vacuoles) catalyses the
breakdown of endoperoxide (-O-O-) bridge of the
drug. This is followed by the generation of highly
reactive free radicals that damage the parasite
membrane.
• Uses ✓ Their use is restricted to the clinical cure
(blood schizonticides) of severe falciparum
malaria including cerebral malaria and in
chloroquine or multidrug resistant malaria.

65. • Miscellaneous

66. • Mechanism of action of Pyrimethamine
• It is structural analogue of pteridine portion of dihydrofolic
acid. So, it blocks the reduction of dihydrofolic acid into
tetrahydrofolic acid by competitively inhibiting the enzyme
dihydrofolate reductase.

67. • Use of Pyrimethamine • It is used in
combination with sulphadoxine or dapsone in
chloroquine resistant P. falciparum malaria.

68. • It contains naphthoquinone nucleus, used in
combination with proguanil.