Prepared By

Dr. Khalid Ahmad

CHEMOTHERAPY Shadid
Chemistry Department
Islamic university in
madinah
1
INTRODUCTION
Internal treatment of diseases
of microbial origin by the use
of chemical compounds which
have a specific toxicity to the
infecting micro-organisms but
are relatively harmless to the
infected host is known as
Chemotherapy. Salvarsan (dioxy-diamino-arsenobenzol-
dihydrochloride) also called drug “606”
The term Chemotherapy was
coined by Ehrlich 1909, who 2
INTRODUCTION
A therapeutic agent should have following properties :
(1) it should be harmful to the invading micro-organism but
almost harmless or non-toxic to the host.
(2) its action should be localized at the site of the disease.
(3) as far as possible it should be free from side effects.

3
 INTRODUCTION
The success of Chemotherpy depends upon the nature of the
interaction of the drug with the invading organism and the mode
by which the latter responds to its altered environment.
A drug is said to be ‘bacteriostatic’ when it stops further growth
and multiplication of bacteria and it is said to be ‘bactericidial’
when stops outrightly kills them.
The discovery of antibacterial activity of sulphanilamide in 1934
and of Penicillin in 1940 marked the opening of a new era in the
treatment of systemic microbial infections. Before these, means of
combating with microorganisms were very limited. 4
 4 1

SULPHONAMIDES
H2N SO2 NH
sulphanilamide

Domagk 1934 discovered that Prontocil, a dye, was

remarkably effective against streptococcal and
staphyllococcal infections in humans. It was shown that
the antibacterial action of Prontosil was due to its
transformation in the body into sulphanilamide This led
to the synthesis of an enormous number of
sulphonamide drugs, several of which had broader
antibacterial activity and lower toxicity than the parent
compound sulphanilamide. Before the arrival of
Prontocil
antibiotics, they were the main drugs in the treatment of
5
 SULPHONAMIDES (p-
aminobenzenesulphonamide)
The important sulphonamides are listed in the following
table.
Su - stands for the sulphonamideH N4group. SO NH
1
2 2

sulphanilamide

Su N
Su N Su N N NH
Su
N Su C
N NH2
S
CH3
Sulphaquani Sulphathiazo Sulphadiazin Sulphapyridi Sulphameraz
dine le e ne ine
6
SULPHANILAMIDE (p-
aminobenzenesulphonamide)
Sulphanilamide maybe prepared from acetanilide and
Chlorosulfuric acid :

ClSO3H NH3
CH3CONH CH3CONH SO2Cl

P-chloroacetamidobenzenesulphonic acid

NaOH
CH3CONH SO2NH2 NH2 SO2NH2

7
 SULPHONAMIDES
Most of the sulpha drugs, at their concentrations used in
chemotherapy, are only bacteriostatic in their action.
They prevent multiplication of the infecting organism and
thus allow the normal defense mechanism of the host to
eradicate the infection.
The advent of antibiotics a few years later marked an
even greater
advance in chemotherapy.
8
 ANTIBIOTICS

Antibiotics are substances produced ( metabolites ) by

microorganisms which are harmful to other micro-organisms growing
in the same
medium and inhibit the growth or activity of certain bacteria ( bacterio
static effect ) or kill the bacteria ( bactericidal ). Thus, one microbe is
put against another microbe.
Alexander Fleming, in 1929, observed that a mould, Penicillium
notatum, produced a substance that possessed potent bacteriostatic
properties.
9
 ANTIBIOTICS
Penicillin had a very high activity against
Gram positive organisms including
Staphylococci, Streptococci, Pneumococci,
Gonococci etc.
It was first used clinically in 1941 and the
results were so astonishing
that world-wide interest was roused
immediately.
This stimulated search for other antibiotics,
and since 1940, a large number of antibiotics
have been isolated from fermentation mold of
bacteria and actinomycetes.
In 1944, Waksman isolated Streptomycin from
a strain of actinomycetes, streptomyces 10
 ANTIBIOTICS: PENICILLIN
Penicillin: There are at least six natural penicillins,
isolated from different penicillium moulds.
The general structure of all penicillins is:
Cis stereochemistry

amide Thiazolidine ring

β-Lactam

Carboxylic acid
Broken by Betalactamase enzyme

They differ only in the nature of R. Different Penicillins

are shown in the following table.
Penicillin has almost no toxicity but sometimes allergic reaction is 11
Active material Inactive (Major Determinant)
Raw material for other Responsible for
penicillin hypersensitivity

12
13
14
 DRUG ACTION OF
ANTIBACTERIALS
The present concept of the mechanism of action of antibacterials
is that they act by ‘selective interference’ with certain phases of
microbial metabolism. This ‘selective toxic action’ can occur in
either of the two ways:

(i) indirectly, by inhibiting the synthesis of necessary nutrient

which is essential for pathogenic microbes. Consequently, a
number of subsequent metabolic processes will be blocked for
want of this essential nutrient. or,

(ii) directly, by interfering with the structure or metabolism of

15
 DRUG ACTION OF
ANTIBACTERIALS
For example, p-amino benzoic acid ( PABA ) is an essential
metabolite for bacteria that is involved in the synthesis of folic
acid (a member of vitamin B complex group) which is an essential
growth factor for some microorganisms. PABA and Sulphanilamide
have similar structures. Because of this structural resemblance,
bacteria mistakingly consumes sulphanilamide. Sulphanilamide
cannot perform the function of PABA. On the other hand,
sulphanilamide immobilizes some essential metabolite of the
micro-organism by irreversible combination with it or by blocking
some enzyme system involved in the utilization of PABA. This is
16
 DRUG ACTION OF
ANTIBACTERIALS
Most of the antibiotics exert their toxic action on bacteria
by impairing either:
(i) structure and/or synthesis of the bacterial cell wall.
or (ii) the function and/or synthesis of the cytoplasmic
membrane
or (iii) the intracellular synthesis of proteins and/or nucleic
acid Protein synthesis is a fundamental process in all
living cells and those antibiotics that interfere with the
synthesis of proteins within bacterial cells are effective
against both Gram positive and Gram negative bacteria 18
Based on their mode of action, the drugs are grouped into main classes.
Example Action Class
Acetanilide, Phenacetin, Codeine Aspirin, relieve pain and lower Analgesics and
Paracetamol etc. body temperature antipyretics
Chlorofrom, Cocaine, Ether, Cyclopropane induce unconsciousness for a Anaesthetics
Nitrous oxide, Procaine, Novocaine Benzocaine limited period.
etc.
Magnesium hydroxide, Al-Na silicate neutralise from or remove Antacids acid
gastric contents
Bacitracin, Chloromycetin, Penicillin, antimicrobial agent Antibotics
Streptomycin, Tetracyclin ( Aureomycin ),
Oxytetracyclin ( Terramycin ) Erythromycin,
Neomycin etc.
Benadryl, Promethazine etc. antagonise and reduce the Antihistamines
intensity of allergic and
anaphylactic reactions
Digitalis, Amylnitrate, Glyceryl trinitrate etc dilate blood vessels Cardiovascular
drugs
Cortisone, Cortisol, Phenyi-butazone, Relieve inflammation Anti inflammatory
Indomethacin.
Caffeine, Amphetamine, Theophylline stimulate or depress CNS Central nervous
system drugs
Example Action Class
Insulin, Thyroxine, Cortisone etc. varried physiological influences Hormones
Liquid paraffin cleans the bowels Laxatives
Barbital, Phenobarbital, Amobarbital, Amitol, produce drowsiness, central Sedatives and
Luminal etc. nervous system, depressants hypnotics
Sulphanilamide, Sulphathiazole, antibacterials Sulphonamides
Sulphaguanidine, Sulphadiazine etc.
Meprobate, Chlorodiazepoxide, Diazepam, Hypnotic and sedative Tranquilizer
Chloropromazine

Thiamine, Riboflavine, Nicotinic acid General health Vitamins and

Nutrients
Chlorpropamide, Tolbutamide decrease blood sugar Oral
hypoglycemic
agents
 SYNTHESES OF SOME
INDIVIDUAL DRAGS
1. Paracetamol : ( p-acetamidophenol or p-acetyl amino phenol). OH

It is a white, crystalline, odorless powder.

Use : It is used as an analgesic and antipyretic. It can relieve headache,
arthritic and other pains arising from muscles and joints, and It is also
known as acetaminophen. It is an intermediate compound in the
preparation of Phenacetin, another analgesic and antipyretic.
Preparation: Paracetamol is prepared as follows.
(i) by reduction of p-nitrophenol with Tin and glacial acetic acid NHCOCH3
(with or without aceticanhydride)
OH OH OH

CH3COOH
3H2
glacial
Phenacetin

NO2 NH2 NHCOCH3

(ii) from p-amino phenol by the action of glacial acetic acid and acetic anhydride. 21
(as shown in
PARACETAMOL OH OH OH

.from p-hydroxy acetophenone( iii)

NH2NH2 Rearrangement
HN3

CO CH3 C N NH2 NHCOCH3

H3C
p-hydroxy acetophenone
p-hydroxy acetophenone hydrazone

H
Mechanism of rearrangement H3 C H3C O
OH

OH N N
H2O

H3C
C OH OH
N NHCOCH3
H2N 22
 SYNTHESES OF SOME
INDIVIDUAL DRAGS
NH2
2. Sulphathiazole : ( N1-2-thiazolyl sulphanilamide )
Use : It is used mainly in more severe infections.

SO2 N
S
H
Preparation : It is prepared by condensing 2-amino-thiazole with p-
acetamido benzene sulphonyl chloride (in dry pyridine)

23
 Preparation: It is prepared by condensing 2-amino-thiazole with p-acetamido benzene
sulphonyl chloride ( in dry pyridine) NHCOCH3
NHCOCH 3

N
dry pyridine
H2N - HCl
S N

SO2Cl SO2 N
NH2 S
H

dil
NaOH

SO2 N
H S

2-amino thiazole is prepared by treating thiourea with a,β- SH

dichloroethyl ether.
CH2Cl NH2
CH2Cl N
H C O CH2 HN

CH3 H C O Thiurea H2N

Cl S 24
 CHLOROMYCETIN( 3 )
Chloromycetin: (chloramphenicol)
Chloramphenicol enjoys the distinction of being the first major antibiotic for
which practical syntheses have been devised. It was initially made by
fermentation from cultures of the soil bacterium, streptomyces venezuelae,
but now is mainly manufactured by synthesis
Preparation
( 1 ) Long and Troutman Synthesis: This is employed in large scale
production of Chloromycetin in competition with the biological process.
Br2
O 2N COCH3 O2N COCH3Br

p-nitro
acetophenone
25
(i) (CH2)6N4
O2N CO CH2NH2
(ii) C2H5OH HCl

(CH3CO)2O
O2 N COCH2 NH COCH3
(NaOAC)

NHCOCH3
HCHO Reduction
O2N CO CH
aq. NaCO3 [(CH3)3CHO]3Al
CH2OH in (CH3)2CHOH
H NHCOCH3
(i) HCl
O2N C C CH2OH
DL-threo (major product) (ii) NaOH
+ DL-Erythro (minor product) OH H
26
 H NH2
Resolution with
O 2N C C CH2OH
(+)- camphor-
sulphonic acid
OH H
DL-threo

H NH2 H NHCOCHCl2
Cl2CHCOOCH3
O2N C C CH2OH O2N  
C C CH2OH

OH H OH H
DL-threo
D-(-) Chloramphenicol

Separation of DL-threo and DL-erythro forms is easily

achieved by crystallization.
Chloramphemicol has two asymmetric carbon atoms
(marked with asterisks * ). Therefore, there are two pairs of
enantiomers possible. Chloramphenicol is D-(-)-threo-1-p-
Nitrophenyl-2-dichloracetamido-1,3-propanediol 27
 CHLOROMYCETIN:
(CHLORAMPHENICOL)
Use: Chloramphenicol is a broad spectrum antibiotic,
active against both Gram positive and Gram negative
bacteria, the typhus fever and certain viruses.
Of the four stereoisomers, only D-threo form is active. It
is a drug of choice for typhoid. Because of serious toxic
effects its clinical use has been sharply curtailed.

It is also interesting to note that Chloramphenicol is the

first natural compound to contain a nitro group, the 28
 SYNTHESIS OF ( 4 )
: PENICILLINS
(1) Synthesis of Penicillins V
Penicillins V

Sheehan et al, carried out the first successful synthesis of penicillins. He

synthesised Penicillin V (Phenoxy methyl penicillin). It involved the following
steps:
(i) t-Butyl phthalimidomalonaldehydate(I) was prepared by condensing
phthalimide with t-butyl chloroacetate, (Gabriel synthesis ), followed by
formylation of a active methylene group (Claisen condensation ).
(ii) Thus, in this compound (I), the amino group was protected by phthalimido
group and one of the -COOH groups (the one later on involved in ring closure)
was protected by t-butyl ester formation.
(iii) The compound (I) was then condensed with D-penicillamine.
(iv) Phthalimido group was then removed by reaction with hydrazine. The use
of this reagent left the ester group intact.
(v) Phenoxy-methyl group was introduced by treatment with phenoxyl acetyl
chloride. 29
 Condensing phthalimide with t-butyl chloroacetate, (Gabriel synthesis), followed by
formylation of a active methylene group (Claisen condensation).

O O O
O CH3 H3C CH
3
CH3
N H Cl KOH N O CH3
O
CH3
O O
Phthalimide t-butyl chloroacetate
CH3
H3C
The amino group was protected by phthalimido group
CH3
O O
-COOH groups (the one later on
O involved in ring closure) was
HCOOEt protected by t-butyl ester
N
NaNH2 formation.
O
O H
30
t-Butyl phthalimidomalonaldehydate
 CH3
H3C

t-Butyl CH3 O
O O H3C CH3
phthalimidomalonaldehydate
O
condensed with D-
penicillamine. N HO
SH
O
O H NH2
D-Penicillamine

CH3
H3C

CH3
O O
O
O
S
N S = N CH CH
CH
ButOOC
O O HN CH COOH
HN CH COOH
31
Phthalimido group was then removed by reaction with hydrazine. The use of this reagent
left the ester group intact.
O
S
S
N CH CH (i) NH2 NH2 Cl H3N CH CH
ButOOC
(ii) HCl
O HN CH COOH ButOOC HN CH COOH

Phenoxy-methyl group was introduced by treatment with phenoxyl acetyl chloride

S H S
Cl H3N CH CH PhOCH2COCl N CH CH
O
ButOOC HN CH COOH
Et3N
O
ButOOC HN CH COOH

32
t-butyl group was removed by hydrolysis with HC1 to give a penicilloic
acid
H S H S
N CH CH dry N CH CH
O O
ButOOC HN CH COOH
HCl
O O O OH HN CH COOH
Penicilloic acid

The final step of cyclisation (formation of (β-lactam ring) was carried out on the K-Salt
of the penicilloic acid with Dicyclohexyl carbodimide (DCC) to get Penicillin V

H S H S
1eq KOH
N CH CH N CH CH
O O
DCC
O OH HN CH COOH O C N CH COOH
O O
Penicillin V
33
 (2) IMPROVED SYNTHESIS
OF PENICILLINS
In the improved synthesis of penicillins, 6-amino-penicillanic acid is first prepared which is then directly
acylated to get ajpenicillin.
It may be noted that, in this route the β-lactam ring is formed before the protecting groups are removed.

(a) Synthesis of 6-amino

O
penicillanic acid :S S
N CH CH (i) PhCHN2
H2N CH CH
ButOOC
(ii) NH2 NH2
O HN CH COOH ButOOC HN CH COOH

S
H2N CH CH (i) Ph3CCl/ Et2NH
dry
HCl (ii) DCC
O OH HN CH COOH
(iii) H2 - Pd

H S S
Ph3C N CH CH HCl H2N CH CH

N CH COOH N CH COOH
O O 34
6-amino penicillanic acid
 (b) Conversion of 6-amino penicillanic acid
into a penicillin;
For example, Penicillin-G can be obtained from 6-
aminopenicillanic acid by treating it with phenyl acetyl
chloride. O
S
H2N CH CH S
C6H5CH2COCl N CH CH
H
N CH COOH - HCl N CH COOH
O O
Penicillin-G

Thus, it may be mentioned here that not only 6-amino-

penicillanic acid has been synthesised but total syntheses
of penicillins has also been achieved. 35
 O
It is also known as Anaesthesin

BENZOCAINE ( ETHYL-p O

-AMINO-BENZOATE ) H2N

Preparation: It is conveniently prepared from p - nitrobenzoic acid by the

(i)following methods.
p - nitrobenzoic acid is first reduced with tin and hydrochloric acid to p -
amino benzoic acid. The latter is then esterified with ethyl alcohol in the
presence of hydrogen chloride.
COOH COOH COOC2H5

Sn/HCl C2H5OH/ HCl

NO2 NH2 NH2

Benzocaine
36
 BENZOCAINE ( ETHYL-p
-AMINO-BENZOATE )
(ii) p-nitrobenzoic acid is first converted into its ethyl ester the latter is
reduced with hydrogen in the presence of Adam’s platinum oxide catalyst.

COOH COOC2H5 COOC2H5

C2H5OH/ H2SO4 H2/PtO2

NO2 NO2 NH2

37
 CHLORPROPAMIDE
(i) Preparation: Synthesis: The synthesis of chlorpropamide has been carried
out by reacting p-chlorosulfonamide with n-propylisocyanate in the presence
of mild base (Scheme 5a).
Side effects: Renal impairment and hypertension other than hypoglycemia is
reported.

Metabolism: The half life period of

chlorpropamide is relatively longer
because of p-chloro substituent which
protects the p - position from
metabolic oxidation. 20% of a dose is
excreted unchanged and remaining
80% is metabolized by omega and
omega-1 type oxidation (Scheme 5b). 38
 CHLORPROPAMIDE
(ii) Preparation : Chlorpropamide is prepared by refluxing p-chlorophenyl
sulphonamide (I) with ethyl chloroformate (II) in the presence of anhydrous K2CO3 in
acetone. Ethyl-( p-chlorophenyl sulphonyl)-
H
carbamate (III) thus formed
SO2NH2 is heated
O with n-propyl amine to
O get
N chlorpropamide.
O
S
(i) anhydrous O O
Cl O
K2CO3 in acetone
Cl (ii) conc. HCl Cl

 NH2CH2CH2CH3

H H
O N N
Use : it is an oral hypoglycemic agent and is S
O O
used for the treatment of stable diabetes.
39
Cl
THANK
YOU
40