Medicinal_chemistry_III.pdf

JYOTHISMATHI INSTITUTE OF PHARMACEUTICAL
SCIENCE
(Medicinal chemistry -III)
Department : Pharmaceutical Chemistry
Subject Code : PS601
Regulation : R-17
Year & Semester : III –II SEM
Prepared by :(S.D.SHANMUGAKUMAR & 3010003 )
Resource ID : Version :
1

UNIT 1- PENCILLINS
Topic Name : HISTORICAL BACKGROUND
1. Pencillins refers to a group of beta –lactam antibiotics used against
bacteria ; especially gram positive organisims.
2. The discovery of pencillin was done by alexander fleming in 1928.
3. The development of pencillin for use of medicine by adelaide born nobel
laureate Howard walter florey.
4. In march 2000, doctors of the San Juan de Dios Hospital in san jose
published manuscripts.
5. Fleming coined the term “ Penicillin’ to describe the filtrate of a broth
culture of the penicillium mold.
6. The chemical structure of pencillin was determined by Dorothy Crow foot
hodgkin in the early 1940’s enabling synthetic production
7. In 1945, Nobel prize was given for fleming for the discovery of pencillin
8

9
UNIT 1- PENCILLINS
Topic Name : CLASSIFICATION
Pencillins are also classified on many ways depending upon the nature and
spectrum activity :
1. Natural ( Biosynthetic) Pencillins : e.g: benzyl pencillin ( Pencillin –G), 2-
Pentenyl pencillin ( Pencillin –F), 3- pentenyl Penicillin, n-pentyl pencillin, n- heptyl
penicillin ( penicillin k), P-hydroxy benzyl pencillin ( pencillin X), Phenoxy methyl
pencillin ( Pencillin V) and zero allergy pencillin.
2. Semi- Synthetic Penicllins : e.g : Ampicillin, amoxycillin, methicillin, nafacillin,
cloxacillin, dicloxacillin, flucloxacillin, carbenicillin, ticarcillin, piperacillin, Mezlocillin and
cyclacillin

10
UNIT 1- PENCILLINS
Topic Name : Based on spectrum of activity
1. Effective against gram –positive bacteria : Benyl pencillin, ampicillin,
oxacillin.
2. Effective against gram – negative bacteria : Temocillin.
3. Broad spectrum pencillins : Methicillin, nafacillin, oxacillin, cloxacillin,
dicloxacillin, Flucloxacillin.
4. Acid resistant Pencillins : Benzathine pencillin, Phenoxy methyl penicillin,
Phenoxy ethyl pencillin, Phennoxy propyl pencillin

11
UNIT 1- PENCILLINS
Topic Name : Based on spectrum of activity
1. Effective against gram –positive bacteria : Benyl pencillin, ampicillin,
oxacillin.
2. Effective against gram – negative bacteria : Temocillin.
3. Broad spectrum pencillins : Methicillin, nafacillin, oxacillin, cloxacillin,
dicloxacillin, Flucloxacillin.
4. Acid resistant Pencillins : Benzathine pencillin, Phenoxy methyl penicillin,
Phenoxy ethyl pencillin, Phennoxy propyl pencillin

12
UNIT 1- PENCILLINS
Topic Name :Chemistry of pencillins
The penicillin structure composed of fused 4- member Beta –lactam ring
with thiazolidine nucleus. It contains three chiral carbon atoms ( C3, C 5, & C6). 6-
Amino penicillaniac acid (6-APA) is the basic skeleton

13
UNIT 1- PENCILLINS
Topic Name : Structure of Benzyl Pencillin
O
NH
O
N
S CH3
CH3
O
O
H

14
UNIT 1- PENCILLINS
Topic Name : Structure of phenoxy methyl pencillin
O NH
O
N
S CH3
CH3
O
O
H

15
UNIT 1- PENCILLINS
Topic Name : Structure of pencillin –X
O
H
NH
O
N
S CH3
CH3
O
O
H

16
UNIT 1- PENCILLINS
Topic Name : Structure of phenethicillin
O
CH3
NH
O
N
S CH3
CH3
O
O
H

17
UNIT 1- PENCILLINS
Topic Name : Structure of oxacillin
N O
CH3
NH
O
N
S CH3
CH3
O
O
H
Cl

18
UNIT 1- PENCILLINS
Topic Name : Structure of dicloxacillin
N
O
CH3
NH
O
N
S CH3
CH3
O
O
H
Cl
Cl

19
UNIT 1- PENCILLINS
Topic Name : Structure of ampicillin
Topic Name : Structure of
NH2
NH
O
N
S CH3
CH3
O
O
H

20
UNIT 1- PENCILLINS
Topic Name : Structure of amoxycillin
NH2
NH
O
N
S CH3
CH3
O
O
H
O
H

21
UNIT 1- PENCILLINS
Topic Name : Structure of piperacillin
O
H
N
H
O
N
N CH3
O
O
NH
O
N
S CH3
CH3
O
O
H

22
UNIT 1- PENCILLINS
Topic Name : Degaradation of Pencillins – step –I
Pencillin in the presence of sulphuric acid it forms penillic acid
NH
O
N
S CH3
CH3
O
O
H
O
O
OH
N N
R
1
S
O
O
H
CH3
CH3

23
UNIT 1- PENCILLINS
Topic Name : Degaradation of Pencillins – step –2
Pencillin with strong acid to form pencillamine and Penilloaldehyde
NH
O
N
S CH3
CH3
O
O
H
O
S
H
CH3
CH3
O
O
H NH2
+
O
NH
O
R
1

24
UNIT 1- PENCILLINS
Penicillin to penicilloic acid to penilloic acid with mercuric chloride it
forms pencillamine and penilloaldehyde
NH
O
N
S CH3
CH3
O
O
H
O
O
NH
O
O
H
R
1
NH
S CH3
CH3
O
O
H
O
R
1 NH
N
H
S CH3
CH3
O
O
H
S
H
CH3
CH3
N
H2
O
O
H
+
O
NH
O
R
1

25
UNIT 1- PENCILLINS
Penicillin add with methanol
NH
O
N
S CH3
CH3
O
O
H
O
S
H
CH3
CH3
N
H2
O
O
H
+
O
NH
R
1
O
O
C
H3
NH
S CH3
CH3
O
O
H
O
O
C
H3
O
R
1

26
UNIT 1- PENCILLINS
Penicillin with PH 6 Penicillenic acid on hydrolysis penaldic acid to
give penamaldic acid to give pencillamine + penaldic acid to form
penilloaldehyde.
R
1
NH
O
N
S CH3
CH3
O
O
H
O
C
H3
C
H3 SH
O
O
H
NH
O
O
N
R
1
O
NH
O
O
H
NH
O
OH
CH3
CH3
S
H
S
H
CH3
CH3
O
O
H
NH2
+
O
R
1 NH
O
OH
O
O
NH O
R
1

27
UNIT 1- PENCILLINS
Topic Name : Synthesis of benzyl penicillin
O
OH
O
OH
O
O
O
NH
O
O
N
O
O
K
N
O
O
O
O
+
CH3
C
H3
C
H3
SH NH2
O
OH
N
H2
O
N
S
O
O
H
CH3
CH3
O
NH
O
N
S
O
O
H
CH3
CH3

28
UNIT 1- PENCILLINS
Topic Name : Mechanism of action
1. Beta –lactam antibiotics act by inhibiting the formation of
peptidoglycan crosses links in the bacterial cell wall.
2. Pencillin binds to the enzyme – Transpepetidase that links the
peptidoglycan molecules in bacteria.
3. In addition, the build up of the peptidoglycan precursors triggers
the activation of bacteria cell wall hydrolysis which further digests the
bacteris existing peptidoglycan

29
Reference Links :
• Book Details : Medicinal chemistry – K. Elango
• Video Link Details : https://www.youtube.com/watch?v=dJAQpyCg8pw;
https://www.youtube.com/watch?v=a81nHSqQuvI
• Please Specify Mtutor
• Video Link details
• (NPTEL, YOUTUBE Lectures and etc.)
• Please specify Mtutor link topic wise(www.m-tutor.com)
• Please specify any course available on <www.coursera.org>,
https://www.coursera.org/search?query=pencillin& - Antibiotic steward ship
and http://neat.aicte-india.org
• Related research work (ongoing & completed) – refer from IEEE Transactions, Elsevier and Springer.
If avaliable : Penicillins_ C764_ 9780123864543.pdf
UNIT 1- PENCILLINS

30
UNIT 1-CEPHALOSPORINS
Topic Name : CEPHALOSPORINS
1. Cephalosporins compounds were first isolated from cultures of
cephalosporium acremonium from a sewer in Sardinian in 1948 by italian
scientist Giuseppe brotzu.
2. Researchers at the sir William Dunn school of pathology at the university
of oxford isolated cephalosporin C
3. The main nucleus of the cephalosporin C is 7- amino cephalosporanic
acid.
4. Modifications of the 7-ACA side chains resulted in the devlopment of
useful antibiotic agent and the first agent cephalothin was launched by Eli lilly
1964.

31
Topic Name :MECHANISM OF ACTION
1. Cephalosporins are bactericidal and have the similar action as other
Beta –lactam antibiotics.
2. It disrupts the synthesis of the peptidoglycan layer of bacterial cell walls.
3. The petidoglycan is transpeptidation with the help of trnaspeptidases
known as pencillin binding proteins
Reference Links :
• Video Link Details : https://www.youtube.com/watch?v=bU2iGzwrQEE
• Related research work (ongoing & completed) – refer from IEEE Transactions, Elsevier and
Springer.
If avaliable :Cephalosporins_ pharmacology_ and_ chemistry.pdf

32
Topic Name : CHEMISTRY OF CEPHALOSPORINS
1. The nomenclature of cephalosporin is complex when compare than
pencillins due to the presence of double bond in dihydro thiazine ring.
2. Basic nucleus is 7- amino cephalosporanic acid ( 7-ACA)

33
Topic Name : CEPHAM & CEPHALOSPORANIC ACID

34
Topic Name : SEMISYNTHETIC PENCILLINS
1. The semisynthetic cephalosporins has got the following advantages over
natural pencillin’s
 Increased acid stability
 Better oral absorption
 Broad antimicrobial spectrum
 Increased activity against resistant microorganisms
 Decreased allergenicity
 Increased tolerance.

35
Topic Name : Classification of cephalosporins
1. Based on generations :
 First generation : Cefacetrile, cefalexin, cefadroxil, cefaloglycin, cefalonium,
cefaloridine, cefalothin, cefapirin, cefatrizine, ceftezole.
 Second generation : Cefonicid, cefprozil, cefuroxime, cefuzonam, ceflaclor,
cefamandole, ceforanide, cefbuperazone, cefmetazole, cefotetan and cefoxitin.
 Third generation : Cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet,
cefotaxime, ceftiolene, ceftriaxone, ceftazidime, cefpiramide, cefsulodin,
ceftriaxone,
Fourth generation : Cefclidine, Cefepime, cefluprenam, cefosils, cefozoporan,
efiprome, cefquinome.
Yet to be classified : Cefaclomezine, cefaloram, cefaparole, cefcanel,
cefedrolor, cefempidone, cefetrizole, cefivitril, cefusmide, ceftioxide, ceftobiprole,
cefuracetime.

36
Topic Name : structural classification of cephalosporins
First generation cephalosporins : Cefaloridin
N
+
CH3
S
NH
O
N
S
O
O
H

37
Second generation cephalosporins : cefprozil
O
H
NH2
O
NH
O
N
S
O
O
H
CH3

38
Third generation cephalosporins : cefotaxime
N
S
N
H2
N O
CH3
NH
O
N
S
O
O
H
CH3

39
Third generation cephalosporins : cefotaxime
N
S
N
H2
N O
CH3
NH
O
N
S
O
O
H
O
CH3

40
Fourth generation cephalosporins : cefepime
N
+
CH3
N
S
N
H2
N O
CH3
NH
O
N
S
O
O
H

41
Topic Name : Synthesis of 7-ACA from cephalosporin C
NH
O
N
S
O
O
H
O
O
CH3
O
NH2
O
O
H
S
N
O
O
CH3
O
O
H
O
NH
O
N
+
N
O
OH
O
O
O
H
N
O
N
S
O
O
H
O
O
CH3
N
H2
O
N
S
O
O
H
O
O
CH3
+ O
H2

42
Topic Name : Synthesis of cefazolin
N
+
N
N
N O
Cl
+
N
H2
O
N
S
O
O
H
O
O
CH3
+ Cl
H
N N
N
N
O
NH
O
N
S
O
O
H
O
O
CH3
+
S
N N
CH3
S
H
N
N
N
N
+
O
NH
N
O
S
O
O
H
S
N N
CH3

43
Topic Name :Degradation of cephalosporins
O
NH
O
N
S
O
O
H
R
1
R
1
N
H2
O
N
S
O
O
H
R
1
O
NH
O
N
S
O
O
H
R
1
OH
+ O
H2
+ O
H2
N
H2
O
N
S
O
O

44
Topic Name : Comparison between 7- ACA and 6-APA
1. Isolation : Large quantities of 6- APA is isolated from pencillium cultures by
the addition of acyclases. /7-ACA is obtained by the hydrolysis of
cephalosporin C.
2. Source : Hydrolysis of pencillins with amidases gives 6-APA/ Hydrolysis of
cephalosporins with acylases gives 7- ACA.
3. Commercial use : Semisynthetic pencillins are prepared from 6-APA by
suitable modifications at acyl amino side chain./ Semi synthetic
cephalosporins are prepared by acylation of C-7 and substitution of acetoxyl
methyl group at c-3.
4. Stability : Less stable towards acids/ More acid stable

45
Reference Links :
• Video Link Details https://www.youtube.com/watch?v=rpMGC__92wE
If avaliableCephalosporins_ pharmacology_ and_ chemistry.pdf

46
UNIT 1-Betalactamase
inhibitors
Topic Name : β-lactamase inhibitors
1. β-lactamase inhibitors inhibit β- lactamase, an enzyme which is
responsible for the opening of the β-lactam ring of the pencillins and thus
inactivates them.
2. Clavulanate potassium : 3- ( 2- hydroxyethylidene-7-Oxo -4-oxa -1-
aza bicyclo ( 3.2.0) heptane – 2- carboxylic acid potassium salt).
O
N
O
OH
O
O
K

47
UNIT 1-Betalactamase
inhibitors
Topic Name : Tazobactam
3- methyl -7-oxo -3 –(1H-1,2,3 Triazol -1yl methyl) – 4-thia -1-azabicylo (3.2.0)
heptane -2- carboxylic acid.
O
N
S
CH3
N
N
N
O
O

48
UNIT-1-Monobactams
Topic Name : Monobactams
1. Monobactams are parenteral beta-lactam antibiotics
2. Aztreonam is available monobactam – Pseudonomas aeruginosa

49
Reference Links :
• Video Link Details https://www.youtube.com/watch?v=e6Ei6rBDaPo
If avaliable : thij00055-0077.pdf
UNIT-1-Monobactams

50
Tutorial Problems :
MCQ's :
1. The common structure feature of pencillins and cephalosporins is
-------------------- a) Thiazolidine ring b) β-lactam ring c)
Dihydrothiazine ring d) Amino acyl side chain Ans : b
2. Which of the following is true for 7-ACA ?
A) it contains 6- membered ring b) the 6- membered ring is
called dihydrothiazine ring c) The dihydrothiazine ring contains
unsaturation between C-2 and C-3. d) All of the above ans: c
3. Which of the following is an orally active third generation
cephalosporins? A) cefamadole b) Cefotetan c) Cefmetazole d)
All of the above. Ans : d
4. Hydrolysis of cephalosporins with strong acid gives ----------
a) More resistant to β-lactamases b) equally effective against gram
positive and gram –negative organisms c) Highly acid labile
compared to pencillins d) None of the above. Ans : b
UNIT-1- PENCILLINS,
CEPHALOSPORINS AND BETA
LACTAMASE INHIBITORS

51
UNIT-1- PENCILLINS,
CEPHALOSPORINS AND BETA
LACTAMASE INHIBITORS
Tutorial Problems :
Universities & Important Questions :
1. Write a note on discovery of Pencillin?
2. Write the chemistry of pencillins?
3. Write a short note on semi synthetic penicillins?
4. Write a detailed note on β-lactamase inhibitors?
5. Write detailed note on classification and chemistry of cephalosporins?
6. Write a note on degaradation of cephalosporins?
7. Explain the comparison between penam and cepham?

52
UNIT-1- AMINO GLYCOSIDE
ANTIBIOTICS
Topic Name : Amino glycoside antibiotics
1 Aminoglycoside antibiotics are from the Actinomycetes particularly from the genus
Streptomyces.
2 Many antibiotics isolated from the genus – streptomycin
3 All the structures consists of amino sugars linked glycosidically
4 Amino glycoside antibiotics are broad –spectrum antibiotics, particularly effective
against gram – negative bacilli, gram – negative and gram –positive cocci except
staphylococci.
5 Streptomycin is particularly effective against Mycobacterium tuberculosis

53
ANTIBIOTICS
Topic Name : Mechanism of action of Amino glycoside antibiotics
1 They act directly on the bacterial ribosome to inhibit the intiation of protein synthesis
and interfere with translation of the genetic message.
2. They act by binding 30S ribosomal sub unit to form a complex which intiate proper
amino acid polymerization.
Reference Links :
• Video Link Details : https://www.youtube.com/watch?v=IPcbQddeJTw
• Related research work (ongoing & completed) – refer from IEEE Transactions, Elsevier and
Springer. Aminoglycosides_ Mechanisms_ of_ Action_ and_ Resistanc.pdf
If avaliable :

54
ANTIBIOTICS
Topic Name : Streptomycin ( Ambistryn)
1. Streptomycin is produced by the culture of Streptomyces griseus
2. It is a white, odorless, hygroscopic powder.
3. It is freely soluble in water, slightly soluble in alcohol and insoluble in most
of organic solvents.
O
OH
NH
C
H3
OH
OH
O
O
O
H
O
H
CH3
H
H
H H
H
O
NH
NH
NH2
H
NH
NH
N
H2
OH
OH
H H
H
H
H

55
ANTIBIOTICS
Topic Name : Streptomycin hydrolysis( Ambistryn)
streptomycin → strepitidine + streptobiosamine → streptamine + N-methyl
glucosamine

56
ANTIBIOTICS
Topic Name : Neomycin B
1. Neomycin is mixture of three substances isolated from streptomyces fradiae
2. Three components A,B, and C have been separted by counter – current
distribution.
3. Neomycin A is a diasacchride which is common degradation product of Neomycin
B and C.
H
O
O
H
NH2
O
H
H
H
OH
H
H
NH2
H
O
H
H
H
H
H H
NH2
H
H
O
O
H
OH
H
O
H
H H
O
H
NH2
H
N
H2
OH
H
H
O
H

57
ANTIBIOTICS
Topic Name : Kanamycin
1. It is isolated from a culture of streptomyces Kanamyceticus
2. They differ in the substituted D- glucose attached glycosidically to the
4th position of the desoxy streptamine ring.
3. Kanamycin A contains 6- amino – 6- deoxy – D- Glucose.
4. Kanamycin B Contains 2,6 – diamino -2,6 – di deoxy – d-glucose.
5. Kanamycin C contains 2- amino -2- deoxy – D- glucose
O
H
H
O
H OH
H
H
R
2
R
1
H
O
H H
OH
H
NH2
H
H H
NH2
H
O
H
O
H
H
H
NH2
H
O
H
H
O
H

58
ANTIBIOTICS
Topic Name : Structure activity relationship of aminoglycosides

59
UNIT-1-TETRACYCLINES
Topic Name : Chemistry of tetracyclines
1. Tetracyclines are obtained by fermentation from streptomyces spp.
2. They are derivatives of an actahydro naphthacene, a hydrocarbon system that
comprises four annulated six member rings.
3. The first member of the tetracyline group of antibiotic is chlortetracycline from a
culture of streptomyces aeurofaciens.
4. The stereochemistry of the tetracycline is very complex.
5. Carbon atom 4, 4a, 5, 5a, 6 and 12a are potentially chiral depending on
substitution.
6. Tetracyclines are amphoteric compounds forming salts with either acids and
bases. It forms zwitter ions in natural solurtions.

60
Topic Name : structure of tetracyclines
S.No Name R1 R2 R3 R4
1. Tetracycline H OH CH3 H
2. Oxytetracycline H OH CH3 OH
3. DOXYCYLINE H CH3 H OH
4. Minocycline N (CH3)2 H H H

61
Topic Name :Epimerization of tetracyclines
1. The tetracycline is their ability to undergo epimerization at C4 in solutions
of the intermediate PH range.
2. These isomers are called as epi tetracycline.

62
1. Tetracyclines are specific inhibitors of bacterial protein synthesis.
2. They bind to the 30S ribosomal subunit and therby prevent the binding of
amino acyl t RNA to the m RNA ribosome complex.
Spectrum of activity : Tetracyclines are broad spectrum of activity against
gram positive and gram negative bacteria. Spirochetes, mycoplasma, chalmydiae.

63
Topic Name : Tetracycline
1. Chlortetracycline on controlled catalytic hydrogenolysis gives tetracycline.
2. It is also obtained from fermentation of streptomyces spp.
3. It is broad spectrum antibiotic used in the treatment of bacterial infections
of respiratory system, genito urinary system and gastro –intestinal system.
OH O OH O
OH
O
NH2
N
CH3
C
H3
H
OH
CH3
O
H

64
Topic Name : oxyTetracycline
1. It is isolated from streptomyces rimosus.
OH O OH O
OH
O
NH2
N
CH3
C
H3
H
OH
CH3
O
H
OH

65
Topic Name : Doxycycline
1. It is produced by catalytic hydrogenation of methacycline. The 6α – methyl
epimer is 3 times as active as β- isomer.
OH O OH O
OH
O
NH2
N
CH3
C
H3
H
OH
CH3
OH
OH
CH2
O
H
OH
OH O
H
OH
O
N
CH3
CH3
OH
O
NH2
OH O OH
OH
OH
NH2
OH
OH
N
CH3
CH3
OH
H
CH3
H

66
Topic Name : Minocycline
1. The most potent tetracycline currently used in therapy. It is obtained by
reductive methylation of 7- nitro -6- demethyl -6- deoxy tetracycline.
OH O OH O
OH
O
NH2
N
CH3
C
H3
N
C
H3
CH3
H H
OH

67
Topic Name : Degradation of tetracyclines
OH O OH O
O
NH2
OH
OH
N
CH3
CH3
H
OH
H
C
H3
OH
CH3
O
OH
O
OH
CH3
OH
OH
OH
O OH
OH
+
O OH
OH
OH
OH
OH
C
H3
OH O OH
H
OH O
O
NH2

68
Topic Name : Structure activity relation ship of tetracyclines
1. Functional groups at position 5,6 and 7 rings B, C,D in tetracyclines can be
removed without drastically altering antimicrobial properties.
2. Conversion of carboxamide group to nitriles causes a 20 fold loss of
activity though some carboxamide methyl amines are highly active.
3. Epimerization of C5a and C4 dehydrogenation ( C5a, C11a) results in the
loss of activity.
4. The monomeythyl amino and trimethyl amino analogues are relative
inactive.

69
Reference Links :
• Video Link Details : https://www.youtube.com/watch?v=Zfoa4BzjClM
• Please specify any course available on <www.coursera.org>, https://www.coursera.org/search?query=pencillin& -
Antibiotic steward ship
If avaliable :Tetracycline_ Classification_ Structure_ Activity_ Rel.pdf

70
UNIT -1- TETRACYCLINES &
AMINO GLYCOSIDES
Tutorial Problems :
MCQ's :
1. ----------- is regarded as the prototype of all the existing
tetracycline . A) Tetracycline b) Oxytetracycline c)
Chlortetracycline d) Methacycline ans : C
2. ------------- is a semisynthetic derivative of demeclocycline a)
Minocycline b) Methacycline c) Meclocycline d) Both b& C
Ans (a)
3. In tetracyclines, the conjugated trione system extending from C-1 to
C-3 of ring A is acidic is nature with Pka between ---------
a) 1-2 b) 2.8-3.4 c) 3.4-4.8 d) 4-5 ans : ( d).
4. Which of the following group of antibiotics act by interfering with
bacterial protein sysnthesis ?
a) Aminoglycosides b) Macrolides c) Chloramphenicol d ) all of
the above ans .(d).
5. Acid hydrolysis of streptomycin gives streptidine and ---------
a) 2- deoxy streptamine b) dihydrostreptomycin c)
streptobiosamine d) streptamine ans (c)

71
UNIT -1- TETRACYCLINES &
AMINO GLYCOSIDES
Tutorial Problems :
1. Discuss about aminoglycoside antibiotics?
2. Explain the structure activity relationship of aminoglycosides?
3. Write the chemistry of streptomycin?
4. Write a short notes on kanamycin and neomycin?
5. Write the chemistry of tetracyclines?
6. Write the note on epimerization of the tetracyclines?
7. Write a note on degardation of tetracyclines?
8. write a detailed note on mechanism of tetracyclines?

72
UNIT -2-MACROLIDE
ANTIBIOTICS
Topic Name : Macrolide antibiotics are produced by various starins of Streptomyces
1. They have common characterstics : A large non-planar strain less ring.
2. A keto group
3. A glcosidically linked amino sugar
O
O
CH3
OH
CH3
CH3
N
CH3
C
H3
O
O
H
O OH
OH
CH3
C
H3
CH3
O
H
C
H3
C
H3
O
H
C
H3

73
UNIT -2-MACROLIDE
ANTIBIOTICS
Topic Name : Mechanism of action : Macrolide binds to 50s sub unit of the bacterial
ribosome to prevent the translocation step of bacterial protein synthesis. It does not
bind to mammalian ribosome.

74
UNIT -2-MACROLIDE
ANTIBIOTICS
Topic Name : Erythromycin – Erythromycin was isolated form a culture of
streptomyces erythreus
2. It is a mono-acidic base which on hydrolysis gives a basic sugar
desosamine and a neutral sugar cladinose.
O
O
CH3
C
H3
OH
CH3
O
O
N
CH3
C
H3
CH3
O
H
O
O
OH
CH3
OH
C
H3
C
H3
OH
C
H3
O
H
C
H3
O

75
UNIT -2-MACROLIDE
ANTIBIOTICS
Topic Name : Clarithromycin : It is a 6-methyl ester of erythromycin
1. It is prepared by simply methylating erythromycin -6- hydroxyl group.
2. It inhibits cytochrome P450 oxidase and thus potentiates the actions of
drugs metabolized by these enzymes..
O
O
CH3
C
H3
OH
CH3
O
O
N
CH3
C
H3
CH3
O
H
O
O
OH
CH3
OH
C
H3
C
H3
OH
C
H3
O
H
C
H3
O
CH3

76
UNIT -2-MACROLIDE
ANTIBIOTICS
Topic Name : Azithromycin : It is a semisynthetic derivative of erythromycin.
2. It is a 15-membered ring macrolides known as azalides
N
O
CH3
C
H3
OH
CH3
O
O
N
CH3
C
H3
CH3
O
H
O
O
OH
CH3
OH
C
H3
C
H3
OH
C
H3
O
H
C
H3
O
CH3
CH3

77
UNIT -2 - PRODRUGS
Topic Name : Prodrugs : the prodrug is defined as a pharmacologically inactive
compound that is converted in to active drug by chemical or enzymatic process.
1. The prodrug protonosil used for the bacterial infections
2. Protonsil will be converted to 1,2,4 tribromobenzene and sulphasalazine

78
UNIT -2 - PRODRUGS
Topic Name : Utility of prodrugs :
1. Solubility
2. Absorption and distribution
3. site specificity
4. Instability
5. Prolonged release
6. Toxicity
7. Poor patient acceptability
8. Formulation problems

79
UNIT -2 - PRODRUGS
Topic Name : Ideal Requirements of prodrugs
1. The prodrug should be inactive or less active than the parent compound
2. It should not have intrinsic Pharmacological activity
3. The linkage between drug and the carrier must be cleared in vivo
4. The carrier molecule releases in vivo must be non -toxic

80
UNIT -2 - PRODRUGS
Topic Name : Types of prodrugs : Depending upon the constitution, Lipophilicity,
method of bioactivation and catalyst involved in bioactivation, prodrugs were
classified as :
1. Carrier –linked prodrugs
2. Bio-precursors
Carrier –linked prodrugs : Carrier linked prodrugs is a compound that contains
an active drug linked to a carrier group that can be removed enzymatically, such as
ester which is hydrolyzed to active carboxylic acid containg drug.
Carrier –Linker-Drug → Carrier + Linker –Drug → Linker + drug

81
UNIT -2 - PRODRUGS
NH
O
NH
N
S CH3
CH3
O
O
C
H3
O
O
CH3
NH2
O
NH
N
O
S CH3
CH3
O
O
H

82
UNIT -2 - PRODRUGS
Topic Name : Biopercursor –prodrug : Bioprecursors are inert molecule obtained by
chemical modification of the drug but do not contain a carrier.
Nabumetone is an inflammatory drug. NSAIDS normally produce stomach
irritation. This is due to the presence of carboxylic acid group present in the drug.
O
C
H3 O
CH3
O
OH
O
C
H3

83
UNIT -2 - PRODRUGS
Topic Name : Applications of prodrugs :
1. Pharmaceutical applications : Prodrug to improve patient aceptability.
 Prodrug to improve stability.
 Prodrug to overcome formulation problem
2. Pharmaceutical applications :
 Prodrug to improve absorption
Prodrug for site specific drug delivery
 Site directed drug delivery
Site specific bioactivation
Prodrug for slow and prolonged release.
Prodrug to improve membrane transport.
Prodrug for prolonged duration of action.

84
UNIT -2 -ANTIMALARIALS
Topic Name : Malaria is one of the most wise spread diseases caused by protozoan
parasite of genus Plasmodium
These parasites spend an sexual phase in man and sexual phase in female
anopheles mosquito.

85
Topic Name : site of antimalarial gents :
1. Kills the sporozoited injected by the mosquito and prevail the entering of
sporozoites entering the liver. The srugs used in this stage is known as prophylactic
agent.
2. Drugs active against erythrocyctic phase – Amodiaquine, Chloroquine,
quinine, pyrimethamine.
3. Kills the merozoites in the blood and prevent their multiplication known as
suppresive agent – Chlorquine, amodiaquine.
4. Kills the gametocytes before they enter the mosquito and reproduce in to
zygotes eg: primaquine.

86
Topic Name : Structure activity relationship
1. Quinine : Interference with stereochemistry at C9 resulting in epi- series
leads in loss of activity.
2. Destruction of asymmetry at c3 by introducing a double bond at C3.
3. Oxidation of the vinyl group to carboxylic acid destroys all the activity.
4. Replacement of C9-OH group with H or halogen results in the loss of
antimalarial activity.
5.The 6’ methoxyl group seems to be essential for the antimalaraial activity.
6. Opening of the quinclidine ring results in quinotoxines, which is devoid of
any activity.

87
1. 8- Amino quninolines : Although optimum activity in 8- amino quinolines
is obtained with 6-methoxy group
2. Compounds with 6-ethoxy and 6-methyl are having either low activity or
are inactive.
3. Additional substitution on quinoline nucleus tends to decrease both
activity and toxicity.
4. The reduction of quinoline nucleus to 1,2,3,4 tetrahydro analog is
occompained by reduction in activity.

88
Topic Name : Quinine sulphate – Quinine was the first known antimalarial obtained
from Cinchona officinalis
It is a 4-quinoline methanol derivative bearing a substituted quinuclidine
ring.
It has four stereo isomeric chiral centers exist in the molecule at C-3, C-4,
C-8 and C-9.
N
O
CH3
O
H H N
CH2

89
Topic Name : Chloroquine – Chloroquine is the derivative from Plasmodium vivax
& Plasmodium ovale
N
O
CH3
N
H
CH3
N
CH3
CH3
Cl

90
Topic Name : Synthesis of chloroquine.
NH2
Cl
+ H
O
OH Cl
NH O
H
+
Cl
N
H2
N
OH
Cl
N
Cl
Cl
+
C
H3
NH2
N
CH3
CH3
N
Cl
N
H
CH3
N
CH3
CH3

91
Topic Name : Amodiaquine

92
Topic Name : Primaquine

93
Topic Name : Pamaquine

94
Topic Name : quniacrine hydrochloride

95
Topic Name :Mefloquine.

96
Topic Name : cycloguanil

97
Topic Name : Proguanil

98
Topic Name : Pyrimethamine

99
Topic Name : Artesunate

100
Topic Name : Artemether

101
Topic Name : Atovoquone

102
Reference Links :
• Video Link Details :
• Video Link details : https://www.youtube.com/watch?v=aBtxqHEJo9k
• Please specify any course available on <www.coursera.org : https://www.coursera.org/learn/non-communicable-
diseases-in-humanitarian-settings
If avaliable :antimalarial.pdf bray2006.pdf

103
UNIT-2 –MACROLIDE
ANTIBIOTICS ;
PRODRUGS;ANTIMALARIALS
Tutorial Problems :
MCQ's :
1. Erythromycin was isolated from a culture of ------------------------
a) streptomyces erythreus b) streptomyces lincolenisis c) Both a & b d)
all of the above. Ans : a.
2. Clindamycin is a derivative of -----------------------
a) erythromycin b) lincomycin c)polymyxin d) vancomycin ans : b
3. Chloramphenicol is a base known as -------------------
a) 2-amino-P-nitrophenyl1,1 propane triol
b) 2-amino –p- nitrophenyl – 1,1 –propane diol
c) L-adrenaline
d) L-pseudo adrenaline Ans : b.

104
UNIT-2 –MACROLIDE
ANTIBIOTICS ;
MCQ's :
4. An ideal prodrug must be ------------------------------------
a) The prodrug should be inactive or less active than the parent compound.
b) The prodrug should be more active or less active than the parent compound.
c) The prodrug should be less active or more active than the parent compound
d) All of the above ans : a
5. The different types of prodrugs are :
a) Carrier –linked prodrugs
b) Biopercursors
c) Both a & b
d) none of the above.

105
UNIT-2 –MACROLIDE
ANTIBIOTICS ;
MCQ's :
5. Quinine was first isolated from ------------------------
a) Cinchona officinalis b) cinchona succiruba c) cinchona lexandrai
d) all of the above ans : a.
6. Prima quine is a derivative of ---------
a) 8- amino quinolines b) 4- amino quinolines c) 6-amino qunilones
d) 7-aminoquinolines ans : a.
7. The example of sesquiterpene lactone ---------------------
a) Artemether b) artesunate c) arteether d) all of the above.
Ans : d.

106
UNIT-2 –MACROLIDE
ANTIBIOTICS ;
Tutorial Problems :
1. Explain the chemistry of erythromycin and its applications?
2. How will you synthesize the chloramphenicol and illustrate its applications?
3. Elaborate the applications of prodrugs?
4. Explain the SAR of antimalaraial drugs?
5. Write the synthesis of primaquine?
6. Write the chemistry of sesquiterpene lactones?

107
UNIT-3 –ANTITUBERCULAR
AGENTS
Topic Name : Tuberculosis is a chronic infection which is caused by various strains
of Mycobacterium
1. It is transmitted via respiratory route.
2. It mainly affects the lungs but can spread through blood stream and
lymphatic stream to the brain, bones, eyes and skin.
3. In pulmonary tuberculosis, the bacilli reach the alveoli and are ingested
by pulmonary macrophages.
4. Extra pulmonary tuberculosis is much more common in HIV infected
person..
5. The drugs used in the treatment of tuberculosis are called antitubercular
agents.
All first line agents have a standard three letter and a single letter abbreviation as
follows :
1. Ethambutol (E) 2. Isonaizid (H) 3. Pyrazinamide (z) 4. Rifampicin ( R) 5.
Streptomycin (S).

108
AGENTS
Topic Name : Synthesis of Isoniazid
N
CH3
N
O OH
N
O O
CH3
+ N
H2 NH2
N
O
NH
NH2

109
AGENTS
Topic Name : Mechanism of action : It is a prodrug that is activated through an
oxidation reaction catalyzed by an endogenous enzyme catalase peroxidase
The activated INH acylates an enzyme system found exclusively
M.tuberculosis which is essential for the synthesis of mycolic acid.

110
AGENTS
Topic Name : Ethionamide

111
AGENTS
Topic Name : Mechanism of action : Primary drug for treatment of Mycobacterium
tuberculosis. It is most potent and selective of the known tuberculostatic
antibacterial agent. It is effective aginst in the therapy of tuberculosis.
ADR : Anorexia, excessive salivation and metallic taste
Dose : 15-20mg/kg/day

112
AGENTS
Topic Name : Ethambutol

113
AGENTS
Topic Name : Pyrazinamide

114
UNIT-3 –ANTITUBERCULAR AGENTS
Topic Name : Para amino salicylic acid
O OH
NH2
O OH
NH2
N
+
O
–
O
O OH
OH
N
+
O
–
O
O OH
OH
NH2

115
Topic Name : Para amino salicylic acid –Mechanism of action : It acts as
antimetabolite interfering with the incorporation of PABA in to folic acid.
Dose : 200mg/kg in divided dose.

116
Topic Name : Rifampicin

117
Topic Name : Rifampicin inhibits bacterial DNA – dependent RNA polymerase and it
blocks the chain formation of RNA synthesis. It has been suggested that the
aromatic napthalene ring bonds to the DDRP.

118
Topic Name : Rifabutin.

119

120
Topic Name : Cycloserine.
It is an antibiotic isolated from streptomyces species
The compound dimerizes on standing or in solution
Mechanism of action : D-Alanine is an important component of
Peptidoglycan portion of the mycobacterial cell wall.
The enzyme D- Alanine racemase in mycobacterium converts L-Alanine to
D-alanine

121
Topic Name : streptomycin

122
Topic Name :Capreomycin sulphate
3,6-diamino-N-[[(8Z)-15-amino-11-(2-amino-
1,4,5,6-tetrahydropyrimidin-6-yl)-8-
[(carbamoylamino)methylidene]-2-
(hydroxymethyl)-3,6,9,12,16-pentaoxo-
1,4,7,10,13-pentazacyclohexadec-5-
yl]methyl]hexanamide;sulfuric acid

123
Reference Links :
• Video Link details : https://www.youtube.com/watch?v=D-CDjIEPOZs
• Please specify any course available on <www.coursera.org
If avaliable :Classification of antituberculosis drugs.pdf

124
UNIT-3 –URINARY TRACT ANTI-
INFECTIVE AGENTS
Topic Name : Urinary –tract infective agents : A number of organic compounds
obtained by chemcial synthesis on the basis of model compounds have useful
antibacterial activity for the treatment of local, systemic and urinary tract infections.
Quinolone antibacterial drugs have been used since 1964. They are highly
active aginst Streptococcus pneumonia. Fluoroquinolones are used to treat upper
and lower respiratory infections.

125
INFECTIVE AGENTS
Topic Name : Structure activity relationship of quinolones
1. 14, 19 oxo –pyridin – 12 carboxylic acid moiety is essential for antibacterial
activity.
2. The pyridione system must be annulated with aromatic ring.
3. Presence of 4-OXO group is must for activity.
4. Fluorine atom substitution at position 6 associated with enhanced
antibacterial activity
10
15
9
16
8
7
12
13
11
N
14
20
O
23
OH
21
O
19
R
22
F
18
N
1
2
3
N
4
6
5
R
2
17
Molecular Formula: C14H12FN3O3

126
INFECTIVE AGENTS
5
6
10
N
7
9
8
3
2
4
N
1
13
O
17
OH
14
O
15
11
CH3
12
C
H3
16
1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid
Topic Name : NALIDIXIC ACID – Dose : 1g – 4times daily for 1-2 weeks

127
INFECTIVE AGENTS
10
15
9
16
8
7
12
13
11
N
14
18
O
22
OH
19
20
CH3
21
F
17
N
1
2
3
NH
4 5
6
1-ethyl-6-fluoro-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid
Topic Name : Norfloxacin dose : 400mg/kg twice daily

128
INFECTIVE AGENTS
5
6
10
7
9
8
3
2
4
N
1
14
O
23
OH
15
F
22
N
16
17
18
NH
19 20
21 11
12 13
1-cyclopropyl-6-fluoro-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid
Topic Name : Ciprofloxacin - dose : 250-750mg/ bid

129
INFECTIVE AGENTS
F
NH2
Cl
+
CH3
H
O
O CH3
O
O CH3
NH
O
O
CH3
F
Cl
Cl
+
N
O
O
OH
F
Cl
+
NH
NH
N
N
H
N
O
OH
O
F

130
INFECTIVE AGENTS
Topic Name : Enoxacin

131
INFECTIVE AGENTS
Topic Name : ofloxacin

132
INFECTIVE AGENTS
Topic Name : Lomefloxacin

133
INFECTIVE AGENTS
Topic Name : Sparfloxacin

134
INFECTIVE AGENTS
Topic Name : Gatifloxacin

135
INFECTIVE AGENTS
Topic Name : Moxifloxacin

136
INFECTIVE AGENTS
Topic Name : Furazolidone – Dose :100mg -4 times daily uses : It has bactericidal
activity against S.aureus, E.Coli, Salmonella, Vibrio chlorae

137
INFECTIVE AGENTS
Topic Name : Nitrofurantoin – dose :50-100mg – 4 times daily – effective gainst a
majority of urinary tract pathogens including certain strains of E.coli, klebsiells,
proteus sp, aerobacter sp.
N
H2
O
O
H
N
H2
O
NH2
N
NH
NH2
O
O
O
O
N
+
O
–
O
N
O
N
+
O
–
O
N
NH3

138
INFECTIVE AGENTS
Topic Name :Methenamine -1gm 3-4 times a day

139
UNIT-3 –ANTIVIRAL AGENTS
Topic Name : Antiviral drugs are a class of medication used specifically for treating
viral infections. Viruses conducts no metabolic process on their own. They invade
the host cell which may be bacteria, animal or plant cell.
Virus conducts no metabolic process on their own. They invade the host
cell which may be bacteria, animal or plant cell.
Virus does not possess cell wall. It consists of one or more linear or helical
strands of either DNA or RNA enclosed in a shell of protein known as capsid.
Virus→ Adsorption→ Penetration→Uncoating→
Transcription →Translation→ Assembly→ Release.

140
Topic Name : Amantadine – It is a tricyclic symmetric primary amine that inhibits
penetration of RNA virus particle. Uses : Treatment of Parkinson’s disease. Influenza
virus , Para influenza
2
3
1
4
6
5
7
10
9
8
NH2
11
octahydro-2H-2,4-methanoinden-2-amine

141
Topic Name :Rimantadine : It is more effective against influenza A virus. It interferes
with virus uncaoting by inhibiting the release of specific protein.
2
3
1
4
6
5
7
10
9
8
11
N
H2
12
CH3
13
1-(octahydro-2H-2,4-methanoinden-2-yl)ethan-1-amine

142
Topic Name : Idoxuridine : It is a nucleoside containg halogenated pyrimidine and is
an analogue of thymidine. Uses : It is used for the topical treatment of HSV, Keratitis
NH
8
7
9
N
6
10
11
O
15
I
16
5
O
1
4
2
3
13
O
H
14
OH
12
1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodo-3,4-dihydropyrimidin-2(1H)-one

143
Topic Name : Acyclovir : It is a synthetic analogue of deoxy guanosine in which the
carbohydrate moiety is acyclic.

144
Topic Name : Acyclovir : Mechanims of action
Acyclovir → Active acyclovir monophosphate → Acyclovir diphosphate
→ Acyclovir triphosphate → Deoxy guanosine → DNA chain termination

145
Topic Name : Acyclovir : Synthesis of acyclovir
N
N
H
O
N
H2
N
NH
N
N
H N
N
O
O
O CH3
O
N
N
H
N
H2
O
N
N O
OH

146
Topic Name : Ganciclovir – It is analogue of acyclovir, with an additional hydroxy
methyl group on the acyclic side chain

147
Topic Name : Zidovudine - Zidovudine is an analogue of thymidine in which the
azido group is substituted at 3rd – carbon atom of the deoxy ribose moiety. It is
active against RNA tumour viruses that are caustive agents on AIDS and T-Cell
leukemia.
10
11
9
N
6
N
H
8
7
CH3
19
O
18
O
17
5
O
1
4
2
3
15
O
H
16
N
12
N
+
13
NH
14
1-[(2S,3S,5R)-2-(hydroxymethyl)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)oxolan-3-yl]tria
za-1,2-dien-2-ium

148
Topic Name : Didanosine : It is a purine dideoxy mucleoside, which is an analogue
of inosine. It differs from inosine by having hydrogen atom in place of 2’ and 3’
hydroxy groups. It inhibits HIV RT and exerts a virustatic effect on the retroviruses.

149
Topic Name : Zalcitabine..

150
Topic Name :Lamivudine is a synthetic nucleoside analogue that differs from 2’3’ –
deoxy cytidine by the substitution of sulfur atom in place of methylene group at 3’
position. Mecahnism of action : It exerts virustatic effect against retroviruses by
competitively inhibiting HIV-RT after intercellular conversion of the drug to its active
form. Dose : 100mg/OD.

151
Topic Name : Loviride.

152
Topic Name : Delaviridine

153
Topic Name : Ribavirin

154
Topic Name : Saquinavir : it is a carboxamide derivative specifically designed to
inhibit HIV- Protease.

155
Topic Name :Indinavir is a pentanoic acid amide derivative. It causes flank pain,
abdominal pain and malaise.

156
Topic Name : Ritonavir. It causes peptidomimetic inhibitor of HIV-1 and HIV-2
protease.

157
UNIT-3 – ANTITUBERCULAR AGENTS
; URINARY TRACT ANTI-INFECTIVE
AGENTS -ANTIVIRAL AGENTS
Reference Links :
• Video Link Details :C: Users kumar Videos Free YouTube Downloader Mechanism of action of Acyclovir.mp4
• Video Link details : https://www.youtube.com/watch?v=D-CDjIEPOZs ; https://www.youtube.com/watch?v=gPGq3T880Oc
• Please specify any course available on <www.coursera.org :
If avaliable :MedChem10_ Antiviral.pdf

158
UNIT-3 – ANTITUBERCULAR AGENTS
; URINARY TRACT ANTI-INFECTIVE
Tutorial Problems :
MCQ's :
1. Isonaizid is activated through oxidation reaction catalyzed by ---------------
A Catalase peroxidase b) Acylase c) Pyrazine amidase d) All of the above ans : A
2. Pyrazinamide is converted to ---------------
a) PH b) pyrazine amidase c) Pyrazinoic acid d) pyrazine ans :c
3. PAS interfering with the incorporation of PABA to -----------------
a) folic acid b) bacteriostatic c) bactericidal d) none of the above ans a.
4. Acyclovir gets converted -------------------
a) Acyclovir monophosphate b) acyclovir di phosphate c) acyclovir triphosphate
b) All of the above ans : d
5 ) Amantadine is a symmetric tricyclic primary amine that inhibits peneteration of -
------------ virus particle.
a) RNA b) DNA C) MRNA d) All of the above ans : a

159
UNIT-3 – ANTITUBERCULAR AGENTS ;
URINARY TRACT ANTI-INFECTIVE
Tutorial Problems :
MCQ's :
6. Nalidixic acid is particularly effective against ---------------------
a) Gram – Naegative b) Gram –positive C) both d) None of the above. Ans : a
7. Norfloxacin is used in the treatment of ------------------ infections.
a) K.Pneumoniae b) Proteus spp c) S.apidermidis d) S.aureus. Ans : b
8. Furazolidone is a bactericidal activity against -----------------
a) S.aureus b) E.Coli c) Salmonella d) all of the above Ans :d

160
UNIT-3 – ANTITUBERCULAR AGENTS ;
URINARY TRACT ANTI-INFECTIVE
Tutorial Problems :
1. Explain the synthesis of isoniazid?
2. Write the chemistry of first line antitubercular drugs?
3. Write the chemistry of antitubercular antibiotics?
4. Explain the SAR of quinolones?
5. Explain the chemistry of UTI antiinfectives?
6. Explain the synthesis of ciprofloxacin?
7. What are anti viral agents? Classify them with examples?
8. Write the synthetic route of acyclovir?
9. Write the chemistry of antiviral agents?

161
UNIT-4 – ANTIFUNGAL AGENTS
Topic Name : Fungus is a colorless plant lacking chlorophyll.
Fungi that causes disease in humans may be like yeast are called mycotic
infections.
Fungal infections are divided in to two types : 1) superfifcial Mycotic
infections 2) systemic cmycotic infection.
Superficial mycotic infection ; systemic mycotic infection.
Superficial mycotic infections are those occuring on the surface or just below the
skin.
Systemic mycotic infections are those occuring inside the body, such as
lungs and other body organs.
Candida albicans was found as part of the flora of the gastro intestinal
tract and vagina.
Trichophyton rubrum is also a causative agent form ring worm.

162

163
Topic Name : Amphotercin B was isolated from Streptomyces nodosus. It interacts
with ergosterol fungi and forms –trans membrane channel.
Intermolecular hydrigen bond formed among the –OH, -COOH and NH2
group in moiety stabilize the channel in its open form. Amphotericin B has led to the
following formulations : Amphotericin B deoxy cholate ; Amphotericin B colloidal
dispersion ; Amphotericin lipid complex ; liposomal amphotericin B dose : 100-
200mg tablet/ suspension uses : systemic infection
C47H73NO17
(1R,3S,5R,6R,9R,11R,15S,16R,
17R,18S,19E,21E,23E,25E,27E,
29E,31E,33R,35S,36R,37S)-
33-{[(2R,3S,4S,5S,6R)-
4-amino-3,5-dihydroxy-
6-methyloxan-2-
yl]oxy}-1,3,5,6,9,11,17,37-
octahydroxy-15,16,18-
trimethyl-13-oxo-14,39-
dioxabicyclo[33.3.1]nona
triaconta-
19,21,23,25,27,29,31-
heptaene-36-carboxylic
acid

164
Topic Name : Nystatin is an effective topical antifiungal agents. Nystatin is
isoalted from the strains of actinomycete called streptomyces noursei .
Nystatin is a mixture of four different tetraenes. Nystatin A, A3, A2 and
polyfungin B. The aglycone portion of nystatin called nystatinolide consists of a
38- membered macrolide lactone ring containing single tetracene and diene
moieties separated by two methylene groups. Dose : 1-4mg/kg/day uses :
Nystatin is a valauable agent for the treatment of local and gastrointestinal
infetcions caused by candida albicans and other candida species.
C47H75NO17
(1S,15S,16R,17R,18S,19E,21E,25E,27E,29E,31E)-33-
{[(2S,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-
methyloxan-2-yl]oxy}-1,3,4,7,9,11,17,37-octahydroxy-
15,16,18-trimethyl-13-oxo-14,39-
dioxabicyclo[33.3.1]nonatriaconta-19,21,25,27,29,31-
hexaene-36-carboxylic acid

165
Topic Name : Natamycin is also known as pimaricin. It is a polyene natural
antibiotic obtained from the cultures of streptomyces natalensis
The Natamycin structure consist of 26- membered lactone ring containing
a tetraene chromophore, an α, β –unsaturated lactone carbonyl group, three
hydroxyl groups, a carbosyl group. Dose : 100mg/4 times daily use : Natamycin is
active against yeast and fungi including candida, Aspegillus, cephalosprorium,
pencillium and fusarium spp.
C33H47NO13
(1R,3S,5R,7R,8E,12R,14E,16E,18E,20E,22R,24S,25R,2
6S)-22-{[(2R,3S,4S,5S,6R)-4-amino-3,5-
dihydroxy-6-methyloxan-2-yl]oxy}-1,3,26-
trihydroxy-12-methyl-10-oxo-6,11,28-
trioxatricyclo[22.3.1.0⁵,⁷]octacosa-
8,14,16,18,20-pentaene-25-carboxylic acid

166
Topic Name : Griseofulvin is an example of spiro compound. It is isolated from the
fungus Pencillium griseofulvum. Mechanism of action : Griseofulvin inhibits fungal
mitosis by disrupting the mitotic spindle through interaction with polymerized
tubules. By interfering with tubulin polymerization.
Dose : 05-1g daily single or divided dose.
Use : Systematically it is used for the infections caused by ring worm in body, hair
and nail.
C17H17ClO6
(2S,6'R)-7-chloro-
2',4,6-trimethoxy-6'-
methyl-3H-spiro[1-
benzofuran-2,1'-
cyclohexan]-2'-ene-
3,4'-dione

167
UNIT-4 – AZOLE ANTIFUNGAL AGENTS
Topic Name : Azole antifungal agents are the largest class of antifungals available.
Azoles are five membered aromatic rings containing either two nitrogen
(Imidazole) or three nitrogen ( Triazole) . Azoles can be further classified as :
1. Imidazole containing azoles : Clotrimazole , oxiconazole, lanoconazole,
ketoconazole, tioconazole.
2. Triazole contaiing azoles : Fluconazole, voriconazole, terconazole,
itraconazole, posaconazole.
Mechanism of action ; All azoles act by imnhibiting ergosterol biosynthesis through
the inhibition of 14-α-methyl group.
Squalene → Sqaulane epoxide → Lanosterol → ergosterol.

168
Topic Name : Structure activity relationship :
1. A basic imidazole or 1,2,4 triazole with Pka value of 6.5 -6.8
2. N3 of imidazole and N4 of imidazole of triazole bimds to P450 iron.
3. The most active azoles have fluoro in the structure.
4. Ring susbtitution at other position makes the azole inactive.
5. The big non-polar part resembles the steroid molecule in binding to the
enzyme..

169
Topic Name : Clotrimazole It is effective against tinea pedis, tinea cruris, tinea
capitis, tinea vesicular and vulvo vaginal candidiasis
Dose : 100mg/daily
5
N
1
4
2
N
3
6
13 15
16
14
17
18
19
20
24
21
23
22
9
8
10
7
11
12
Cl
25
1-[(3-chlorophenyl)(diphenyl)methyl]-1H-imidazole

170
Topic Name : Econazole - 150mg pessaries once daily. Uses : It is used for the
topical tinea infection and cutaneous candidiasis
C18H15Cl3N2O
1-{2-[(4-
chlorophenyl)methoxy]-2-
(2,4-dichlorophenyl)ethyl}-
1H-imidazole

171
Topic Name : Oxiconazole – It is used for the treatment of tinea pedis, tinea
corporis and tinea capitis.
C18H13Cl4N3O
(Z)-[1-(2,4-
dichlorophenyl)-2-
(1H-imidazol-1-
yl)ethylidene][(2,4-
dichlorophenyl)metho
xy]amine

172
Topic Name : Ticonazole
C16H13Cl3N2OS
1-{2-[(2-chlorothiophen-3-yl)methoxy]-
2-(2,4-dichlorophenyl)ethyl}-1H-
imidazole

173
Topic Name : Miconazole
5
N
1
4
2
N
3
6 7
O
8
9
14
13
15
12
10
11
Cl
22
Cl
23
20
19
21
18
16
17
Cl
24
Cl
25
1-{2-(2,5-dichlorophenyl)-2-[(2,5-dichlorophenyl)methoxy]ethyl}-1H-imidazole

174
Cl
Cl
O
CH3
+ Br Br
Cl Cl
O
CH3
+
NH
N
+
Cl
Cl
Cl
N
N
O
Cl Cl
Cl Cl
Topic Name : Miconazole - synthesis

175
Topic Name :Ketoconazole : It is a broad spectrum imidazole antifiugal agent used
for systemic fungus infection.
It is a powerful inhibitor of CYP3A4 and causes interaction with drugs.
C26H28Cl2N4O4
1-[4-(4-{[2-(2,4-
dichlorophenyl)-2-(1H-imidazol-
1-ylmethyl)-1,3-dioxolan-4-
yl]methoxy}phenyl)piperazin-1-
yl]ethan-1-one

176
Topic Name : Terconazole
C26H31Cl2N5O3
1-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-
2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy}phenyl)-4-
(propan-2-yl)piperazine

177
Topic Name : Itraconazole dose : 100mg/daily for 15 days dose : 40 mg -20mg
bed time
C35H38Cl2N8O4
1-(butan-2-yl)-4-{4-[4-(4-
{[(2R,4S)-2-(2,4-dichlorophenyl)-2-
[(1H-1,2,4-triazol-1-yl)methyl]-1,3-
dioxolan-4-
yl]methoxy}phenyl)piperazin-1-
yl]phenyl}-4,5-dihydro-1H-1,2,4-
triazol-5-one

178
Topic Name : Fluconazole : It has two advantages over other antifungal agents.
Dose : 50-100mg/daily uses : It is used to control oesophageal and
oropharyngeal candidiasis
C13H12F2N6O
2-(2,4-difluorophenyl)-1,3-
bis(1H-1,2,4-triazol-1-yl)propan-
2-ol

179
Topic Name : Natifine hydrochloride. 250mg/oD. Duration : 2-4 weeks ( Tinea
cruris), 4 weeks ( Tinea corporis), 6 weeks ( Tinea pedis).
Uses : Topical antifungal agent effective against Tinea pedis, Tinea corporis,
Tinea cruris.
C21H21N
methyl(naphthalen-1-ylmethyl)(3-
phenylprop-2-en-1-yl)amine

180
Topic Name : Tolnaftate - 1% gel for 2-6 weeks .Uses : Fungicidal effective against
dermatophytes, athelet’s foot.
C19H17NOS
N-methyl-N-(3-methylphenyl)-1-
(naphthalen-2-yloxy)methanethioamide

181
Topic Name : Tolnaftate - Synthesis
OH
+ Cl
Cl
O
O
S
Cl
+
CH3
NH
CH3
O
+
SH
N
CH3
CH3

182
UNIT-4 – ANTIPROTOZOAL AGENTS
Topic Name : Amoebiasis is a protozoal disease caused by protozoan Entamoebia
histolytica.. Amoebic infections generally remain confined to the intestine, where
they may give rise to dysentry.
Classification :
1) Drugs used in intestinal amoebiasis : Diloxanide furroate, Iodoquinol,
atovaquone.
2) Drugs used in extra intetinal amoebiasis : Emetine, de hydro emetine.
3) Drugs used for both intestinal and extra intestinal amoebiasis :
Metronidazole, Tinidazole, orindazole.

183
Topic Name : Metronidazole
5
N
1
4
2
N
3
N
+
10
O
–
12
O
11
6 7
OH
8
CH3
9
2-(2-methyl-4-nitro-1H-imidazol-1-yl)ethan-1-ol

184
Topic Name : synthesis of Metronidazole, Dose : 400-800 mg – three times daily
for 5-10 days uses : Effective amoebcide.

185
Topic Name : Tinidazole – Metallic tasty, nausea and headache. Dose : 2g/day
Uses : Intestinal and hepatic amoebiasis
5
N
1
4
2
N
3
CH3
10
N
+
11
O
–
16
O
12
6
7
S
8
O
9
O
13
14
CH3
15
1-[2-(ethanesulfonyl)ethyl]-2-methyl-5-nitro-1H-imidazole

186
Topic Name : Orindazole - 1.5g as single dose for 3 days – Uses : It is used in the
treatment of crohns disease.
5
N
1
4
2
N
3
CH3
9
N
+
10
O
–
14
O
11
6 7
OH
8
12
Cl
13
1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol

187
Topic Name : Diloxanide furoate (Dyrade –M) – Dose : 500mg/tid, Uses : Drug of
choice for the treatment of symptomatic passers of cysts.
C14H11Cl2NO4
4-(2,2-dichloro-N-methylacetamido)phenyl
furan-2-carboxylate

188
Topic Name : Iodoquinol – 650mg three times daily for 20 days. Uses : It is the drug
of choice for the treatment for infections caused by Entamobea histolytica.
C9H5I2NO
5,7-diiodoquinolin-8-ol

189
Topic Name : Pentamidine
4-{[5-(4-carbamimidoylphenoxy)pentyl]oxy}benzene-1-carboximidamide
C19H24N4O2

190
Topic Name : Atovaquone
C22H19ClO3
2-hydroxy-3-[(1r,4r)-4-(4-
chlorophenyl)cyclohexyl]-1,4-
dihydronaphthalene-1,4-dione

191
Topic Name : Eflorinthine
C6H12F2N2O2
2,5-diamino-2-(difluoromethyl)pentanoic acid

192
UNIT-4 – ANTIHELMENTHICS
Topic Name : Anthelmintics – is restricted to drugs acting locally to expel parasites
from gastrointetinal tract. The worm parasite of man belongs to two phyla :
Nemathelminthes and platyheminthes .
Classification : Anthelmintics are classified based upon the chemical
structure :
1. Piperazines – Diethyl carbamzine citrate.
2. Benzimidazoles : Albendazole
3. Heterocyclics : Oxaminiquine
4. Natural products : Ivermectin.
5. Vinyl pyrimidines : Pyrantel
6. Amide : Niclosamide
7. Nitro derivative : Niridazole
8. Inmidazo thiazole ; Levamazole

193
UNIT-4 – ANTIHELMETHICS
Topic Name : Diethyl carbamzine citrate : 1-6mg/kg/orally. Use : It is a drug of
choice for filariasis
3
2
N
4
N
1
5
6
CH3
7
8
O
9
N
10
11
CH3
12
13
CH3
14
16
17
18
O
25
OH
19
23
O
27
O
H
24
OH
15
20
21
O
26
O
H
22
Molecular Formula: C 16H29N3O8

194
UNIT-4 – ANTIHELMENTHICS
Topic Name : Diethyl carbamzine citrate – synthetic procedure
NH
NH
+ Cl
O
N
CH3
CH3
+ H
O
H
N
N
CH3
O
N
CH3
CH3

195
UNIT-4 – ANTIHELMENTICS
9
8
14
11
13
12
N
10
6
NH
7
4
N
3
2
5
S
1
2-(1,3-thiazol-4-yl)-1H-benzimidazole
Topic Name : Thiabendazole – 25mg/kg twice daily after food.

196
Topic Name : Mebendazole.
C16H13N3O3
methyl N-(6-benzoyl-1H-1,3-benzodiazol-2-
yl)carbamate

197
Topic Name : Mebendazole. It has a broad spectrum activity against nematodes
including whipworm, Pinworm, round worm and hook worm.
O
NH2
+ C
H3
O
O
O
C
H3
O
NH
O
CH3
N
+
O
–
O
O
NH2
NH2
O
NH2
NH2
+ Cl
O
O CH3
O
N
NH
NH
O
O CH3

198
Topic Name : Thiabendazole – Anorexia, abdominal pain, jaundice, tinnitus and
dizziness.
9
8
14
11
13
12
N
10
6
NH
7
4
N
3
5
S
1
2
2-(1,3-thiazol-4-yl)-1H-benzimidazole

199
Topic Name : Niclosamide - anthelmintic of first choice in the treatment of tape
worm, infestations.
14
15
13
16
18
17
OH
20
Cl
21
9
O
10
NH
8
5
4
6
3
1
2
Cl
7
N
+
11
O
–
19
O
12
5-chloro-N-(2-chloro-5-nitrophenyl)-2-hydroxybenzamide

200
Topic Name : Oxamniquine
C14H21N3O3
(7-nitro-2-{[(propan-2-yl)amino]methyl}-
1,2,3,4-tetrahydroquinolin-6-yl)methanol

201
Topic Name : Praziquantel – It is considered as drug of choice for the treatment of
Schistosoma Japonicum
C19H24N2O2
2-cyclohexanecarbonyl-
1H,2H,3H,4H,6H,7H,11bH-piperazino[2,1-
a]isoquinolin-4-one

202
Topic Name : Ivermectin : It is usually extracted from the soil of actinomycete
streptomyces avermitilis , the natural Ivermectins are 16-membered macrocyclic
lactones with broad antinematocidal activity.
C95H146O28
(1'R,2R,4'S,5S,6R,8'R,10'E,12'S,13'S,14'E,16'E,20'R,21'R,24'S
)-21',24'-dihydroxy-12'-{[(2R,4S,5S,6S)-5-
{[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-
methyloxan-2-yl]oxy}-4-methoxy-6-
methyloxan-2-yl]oxy}-5,11',13',22'-tetramethyl-6-
(propan-2-yl)-3',7',19'-trioxaspiro[oxane-2,6'-
tetracyclo[15.6.1.1⁴,⁸.0²⁰,²⁴]pentacosane]-
10',14',16',22'-tetraen-2'-one;
(1'R,2R,4'S,5S,6R,8'R,10'E,12'S,13'S,14'E,16'E,20'R,21'R,24'S
)-6-[(2R)-butan-2-yl]-21',24'-dihydroxy-12'-
{[(2R,4S,5S,6S)-5-{[(2S,4S,5S,6S)-5-hydroxy-
4-methoxy-6-methyloxan-2-yl]oxy}-4-
methoxy-6-methyloxan-2-yl]oxy}-5,11',13',22'-
tetramethyl-3',7',19'-trioxaspiro[oxane-2,6'-
tetracyclo[15.6.1.1⁴,⁸.0²⁰,²⁴]pentacosane]-
10',14',16',22'-tetraen-2'-one

203
UNIT-4 – SULPHONAMIDES
Topic Name : Historical background of sulphonamides
1. Antibacterial sulphonamides are first effective chemotherapeutic
agents used for bacterial infections in humans.
2. The compound P- amino benzene sulphonamide was first
synthesized by Gelmo 1908.
3. In 1932, Gerhard domagk recognized the antibacterial activity of the
azo dye.
4. In 1935, trofouel at pastor institute discovered that protonosil break
down the tissues in to P-amino benzene sulphonamide.
5. The discovery leads to the synthesis of nearly 5500 various
sulphonamides.
6. Sulphonamides inhibit both gram positive and gram – neagtive bacteria
and some enteric bacteria. E.coli

204
Topic Name : Nomenclature of sulphonamides :
Sulphonamides are considered as derivatives of P-amino benzene
sulphonamde. The nitrogen atom of –SO2NH2 is numbered as 1 and The – NH2
group as 4.
3
2
4
1
5
6
NH2
9
S
7
O
8
O
10
N
H2
11
4-aminobenzene-1-sulfonamide

205
Topic Name : Classification of sulphonamides :
1. On the basis of site of action : Sulphonamides for general infections : eg:
Sulphanilamide, sulphadiazine, Sulphamethoxazole, Sulpha doxine, sulpha
pyridine,Sulphathiazole.
2. Sulphonamides for intestinal infections : Phthalyl sulpha thiazole,
Succinyl sulpha thiazole, Sulpha salazine.
3. Sulphonamides for local infections : Sulphacaetamide, mafaenamide,
siver sulpha diazine.
4. Sulphonamides for dermititis : Dapsone, solapsone.
5. Sulphonamides for UTI : Sulpha diazine, Sulphacetamide.
6. Sulphonamide combination : Sulphamethoxazole + trimethoprim
Sulpha diazine+ trimethoprim ; Sulphadoxime + pyrimethamine.

206
Sulphonamides are bacteriostatic in nature.
The microorganisms require Para –Amino benzoic acid for the synthesis of
folic Acid which is essential for the synthesis of DNA & RNA.
N 5, N10 –methylene tetrahydrofolic aicd and N10 formyl tetrahydro folic
acid acts as a co-enzymes in transport of one carbon unit in several biochemical
reactions in humans and microorganisms.
The sulphonamides are structural analogues to PABA that competitively
inhibits the action of dihydropteroate synthetase, preventing the addition of PABA to
pteridine diphosphate and blocking the net biosynthesis of folate co-enzymes.
The conversion of dihydrofolica cid to tetrahydro folic acid is catalyzed by
enzyme dihydrofolate reductase.

208
1. The free amino group is essential for activity. It can be replaced by
groups which can be reconverted it back to free amino group ex: succinyl amido.
2. The sulphanilamide skeleton is the minimal structure requirement for
antibacterial activity.
3. Sulphur should be directly linked to benzene ring.
4. The amino and sulfonyl radical should be 1,4 position; 1,2 and 1,3 isomers
are therapeutically less active.
5. Any substitution on aromatic ring or replacement of benzene ring by
other ring decreases or abolishes the activity.
6. Substitution of heterocyclic aromatic nucleus in N1 position yields highly
potent compound.
7. N1 dissubstitution, leads to inactive compound because one hydrogen is
essential for ionization.

209
1. Maximum antibacterial activity is exhibited by sulphonamides having Pka
values between 6.6 – 7.4.
2. The lipid solubility influences the pharmacokinetic and antibacterial
activity.

210
N
+ O
–
O
NH2
NH
O
C
H3
S
O
O
Cl
NH2
S
O
O
NH
R
1

211
Topic Name : Sulphamethizole – It is used for urinary tract infection
C9H10N4O2S2
4-amino-N-(5-methyl-1,3,4-thiadiazol-2-
yl)benzene-1-sulfonamide

212
Topic Name : sulfisoxazole – Rheumatic fever, UTI infection
C11H13N3O3S
4-amino-N-(3,4-dimethyl-1,2-oxazol-5-
yl)benzenesulfonamide

213
Topic Name : Sulphamethizine – Chronic bronchitis; respiratory tract infections.
C12H14N4O2S
4-amino-N-(4,6-dimethylpyrimidin-2-
yl)benzenesulfonamide

214
Topic Name : Sulphacetamide is a simple acetyl derivative of sulphanilamide.
Sulfacetamide has bacteriostatic effect on a wide range of gram –positive
and gram – negative organisms.
3
2
4
1
5
6
NH2
9
S
7
O
8
O
10
NH
11
12
O
13
C
H3
14
N-(4-aminobenzene-1-sulfonyl)acetamide

215
Topic Name : Synthesis of sulphoacetamide.
NH2
S
O
O
N
H2
+ acetic anhydride
N
H
O
CH3
S
O
O
NH
O
CH3
Selective partial hydrolysis
NH2
S
O
O
NH
O
CH3
Sulphacetamide

216
Topic Name : Sulpha pyridine
C11H11N3O2S
4-amino-N-pyridin-2-ylbenzenesulfonamide

217
Topic Name : Sulpha methoxazole
4-Amino-N-(5-methyl-3-
isoxazolyl)benzenesulfonamide

218
Topic Name : Sulpha methoxazole Uses : It is treatment of meningitis, lower UTI
N
H
O
CH3
S
O
O
Cl
P- acetamido benzene
sulfonyl chloride
+ O
N
CH3
N
H2
3-Amino -5- Methyl Isoxazole
O
N
NH
O
C
H3
S
O
O
N
H
CH3
O
N
CH3
N
H
O
CH3
S
O
O
N
H
Sulphamethoxazole

219
Topic Name : Sulpha diazine – Used in the treatment of Meningitis.
C10H10N4O2S
4-amino-N-(pyrimidin-2-yl)benzene-1-
sulfonamide

220
Topic Name : Mefenide acetate
C7H10N2O2S
4-(aminomethyl)benzene-1-sulfonamide

221
Topic Name : Sulfa salazine It is used to treat ulcerative colitis and rheumatoid
arthritis – Dose : 1-2 gm four times daily.
C18H14N4O5S
2-hydroxy-5-[(E)-2-{4-[(pyridin-2-
yl)sulfamoyl]phenyl}diazen-1-yl]benzoic acid

222
UNIT-4 – FOLATE REDUCTASE
INHIBITORS
Topic Name : Trimethoprim , Agranulocytosis, hemolytic and megaloblastic anemia.
5-[(3,4,5-
trimethoxyphenyl)methyl]pyrimidine-2,4-
diamine
C14H18N4O3

223
INHIBITORS
Topic Name : Trimethoprim ,- Synthesis
O
H
O
CH3
O
CH3
O
CH3
3,4,5 -Trimethoxy
Benzaldehyde
+
OH
O
CH3
O
CH3
O
CH3
3,4,5 - Trimethoxy benzyl
alcohol
Cl
O
CH3
O
CH3
O
CH3
3,4,5 -trimethoxy benzyl
chloride
C
H3
O
O
CH3
O
O
CH3
OH
O
CH3
O CH3
O
C
H3
N
H2
N
H
NH2
N
N
OH
NH2
O
CH3
O
CH3
O
C
H3
O
CH3
O CH3
O
C
H3
N
N
OH
NH2
Trimethoprim

224
INHIBITORS
Topic Name : Cotrimoxazole
C24H29N7O6S
4-amino-N-(5-methyl-1,2-oxazol-3-
yl)benzenesulfonamide;5-[(3,4,5-
trimethoxyphenyl)methyl]pyrimidine-2,4-
diamine

225
UNIT-4 – SULFONES
Topic Name : Dapsone (DDS) – It is an antibacterial mostly common used in
combination with Rifampicin and clofazimine as muti drug therapy for the
treatment of Mycobacterium leprae infections. It is also second line treatment for
prevention of Pneumocystis Pneumonia.
C12H12N2O2S
4-(4-aminobenzenesulfonyl)aniline

226
UNIT-4 – ANTI FUNGAL AGENTS
Reference Links :
• Video Link details https://www.youtube.com/watch?v=4S8-9ik6db0
• Please specify any course available on <www.coursera.org :
If avaliable :Medicinal_ Chemistry_ of_ Antifungal_ drugs.pdf

227
Tutorial Problems :
MCQ's :
1. Antifungal polyene macrolides that prefrentially binds to fungal ergosterol which
alters cellular permeability.
a. Ketoconazole b. Amphotericin B c. Fluctosine d. Griseofulvin ans : b.
2. An azole most commonly used for topical treatment of candidiasis.
a. amphotericin B b. Clotrimazole c. Griseofulvin d. None of the above. Ans.b
3. Nystatin belongs to which class of drug .
a. Polyene b. allyl amines c. echinocardins d. thiocarbamate ans : a
4. Which of the following is not an imidazole antifungal?
a. Clotrimazole b. sertaconazole c. Tioconazole d.Terconazole ans.d
5. Which antifungal drug is associated with shake and bake adverse effects ?
a. Nystatin b.Amphotericin B c. Caspofungin d. mica fungin ans : b

228
Tutorial Problems :
1. Explain the chemistry of Ployene antibitics ?
2. Write the chemistry of Griseofulvin?
3. Write the synthetic route of tolnaftate?
4. Explain the structure activity relation ship of azole antifungal agents?
5. Write the chemistry of econazole?
6. Write the chemistry of itraconazole?
7. Write the chemistry of terconazole?

229
UNIT-4 – ANTI PROTOZOAL AGENTS
Tutorial Problems :
MCQ's :
1. Amoebiasis is a protozoal disease caused by ----------------------
a) Entamoeba histolytica b) Herpes simplex c) Zaricella voster d) All of the
above ans a.
2. Chemotherapy of amoebiasis is to provide drugs to treat ---------------
forms of the disease.
a) Intestinal & Extra intestinal b) Intestinal c) Extra instestinal d) All of the above
ans :a.
3. The dose of metronidazole is ------------------
a) 400-800 mg b) 200-400 mg c) 400-600 mg d) all of the above ans :a
4. Orindazole is used in ---------------------
a) Crohn’s disease b) Treatment of diarrhea c) enteritis d) all of the above
ans : a

230
UNIT-4 – ANTI PROTOZOAL AGENTS
Tutorial Problems :
1. Write the IUPAC name and Chemical structure of ornidazole?
2. Write the synthetic route of metronidazole?
3. Write the chemistry & IUPAC name of orindazole?
4. Write the chemistry of atovaquone?
5. Write the chemistry & IUPAC name of eflorinthine?

231
UNIT-5 – ANTIHELMINTICS
Tutorial Problems :
MCQ's :
1. Anthemintic is restricted to drugs acting locally expel parasites from -----------
a) GI tract b) Urinary tract C) None of the above d) all of the above ans:a
2. Diethyl carbamazine citrate belongs to -------------moiety
a) Piperazine b) Pyridine c) Piperidine d) Pyrazine ans –a
3. Praziquantel is used in the treatment for----------------
a) Schistosoma Japonicum b) Fasciolopsiasis c) Clonorchiasis d)
Opisthorchiasis ans : a
4) Ivermectin contains ------------membered macrocylic lactones
a) 17 b) 18 c) 19 d) 16 ans : d
5) Niclosamide is synthesized from -------------
a) 5-chlorosalicyclic acid b) 6-chloro salicyclic acid c) 7-Chloro salicyclic acid
d) 8- Chloro salicyclic acid ans : a.

232
UNIT-5 – ANTIHELMINTICS
Tutorial Problems :
1. How will you synthesize metronidazole? Explain its pharmaceutical
applications?
2. How will you synthesize mebendazole? Explain its Pharmaceutical
applications?
3. Explain the chemistry of ivermectin?
4. Explain the chemistry of albendazole & Niclosamide?

233
UNIT-5 - Sulphonamides
Tutorial Problems :
MCQ's :
1. Sulphonamides are ---------------------
a) Bacteriostatic b)Bactericidal c) both bactericidal & Bacteriostatic d) None of
the above ans : a.
2. The amino group should be-------------- for antibacterial activity
a) Free b) Bound c) bonded d) none of the above ans :a.
3. The starting compound for the synthesis of sulphonamide --------------
a) Benzene b) Chrysene c) Amino benzene d) Nitro benzene ans :a
4. Sulpha salazine is used in the treatment of ---------------------
a) ulcerative colitis b) Rheumatoid arthritis c) both a &b d) None of the above.
5) Sulphanilamide undergo acetylation it forms -------------------
a) dapsone b) sulpha pyridine c) sulphaisoxazole d) sulphacetamide.

234
UNIT-4 - Sulphonamides
Tutorial Problems :
1. Explain the synthesis of Dapsone?
2. Explain the synthesis of sulphamethoxazole?
3. Explain the chemistry and synthesis of sulphacetamide?
4. Explain the synthesis of trimethoprim?
5. Explain the chemistry of sulphapyridine ?
6. Write the SAR of sulphonamides?
7. Explain the chemistry of co-trimoxazole?

235
UNIT-5 –DRUG DESIGN
Topic Name : Introduction to drug design.
1. The drug discovery process involve the identification of the lead structure
followed by the synthesis of its analogs, and the screening for drug development.
2. Drug discovery and development process such as :
 Lead identification
 Lead optimization
 Pre-clinical lead development
 clinical lead development
Computer assisted molecular design
 Indirect approach
Ligand based drug designing
 QSAR

237
Topic Name : Various approaches of drug design
 Lead identification : Leads can be obtained from natural products, structure
modification of natural products, Biochemical screening, understanding the
process and broad screening of synthetic compounds.
Lead optimization : It involves the identification of lead molecule through the
synthesis and testing of derivatives through structure activity relation ships.
Pre-clinical lead development : Drug formulation experiments, In-vivo studies
in animals, drug metabolism studies, large scale synthesis.
Clinical lead development :It involves the small scale safety and dose ranging
test in healthy human volunteers ( Phase –I) ; short term toxicity and clinical
protocols employing clinical investigations on patients ( Phase –II) ;
Comparative of double blinded studies on patients ( Phase –III).

239
Topic Name : Parameters of QSAR
The biological activity must be function of the chemical structure
BA= f(C) = ∆ BA = f ∆C
QSAR involves the derivatives of mathematical formula which relates the
biological activities of a group of compounds to their measurable physiochemical
parameters
Biological activity = Function ( Parameters).
Biological activity of a drug is a function of chemical features : lipophilicty,
electronic and steric of the substitutents and skeleton of the molecule.
The QSAR approach uses parameters which have assigned to the various
chemical groups that can be used for modify the structure.
1. Lipophilic parameters : Partition co-efficient, chromatographic
parameters, π substitution constant.

240
Topic Name :
1. Lipophilic Parameters : Partition co-efficient, chromatographic
parameters and π – substitution constant
2. Polarizability parameters : Molar refractivity, Molar volume, Parachor
3. Electronic parameters : Hammett constant, Filed and resonance
parameters ; Parmeters derived from spectroscopic data, Charge transfer
constant, dipole moment,Quantum – chemical parameters
4. Steric Paremeters : Taft’s steric constant, vanderwaals radii
5. Miscellanous Paremeters : Molecular weight, Geometric parameters,
conformational entropies, connectivity indices, topological parameters.

241
Topic Name :
1. Lipophilic Parameters : Liphophilicity is defined by the partitioning of a
compound between an aqueous and non – aqueous pahse.
Partition co-efficient and liphophilic substituent constant ( π ).
2. Partition co-efficient : A drug which has to pass through a number of
bilogical memberanes in order to reach its site of action. There were two phases :
Organic/ aqueous system
P= (C) org/ ( C ) aqu.
for easily ionisable drug, correlation must be made as follows :
P= [C] org / [ C] aq (1-α) α = Degree of ionization.

242
Topic Name :
The relationship between P and the drug activity depends on the range of
P values obtained the compounds used :
log 1/C = K1 log P+ K2
K1 and K2 are constants
Experimental determiantion of partition co-efficient :
1. Shake flask method;
2. Chromatographic method..
Chromatographic parameters ; When the solubility of a solute is considerably
greater in one phase than the other. Chromatographic separation can be achieved
with partition co-efficient, silica gel plate. The Rf values are converted in to Rm
value, which are the true measure of lipholicity from the following equation :
Rm = log (1/Rf -1)
To determine the Rm values : Compounds need not be pure
Only trace of materials needed. A wide range of hydrophilic and liphophilic
congeners ; The measurement of practically insoluble analogs.

243
Topic Name :
Liphophilic substituent constant :

244
Topic Name :
hydrophobic fragmental constants f:

245
Topic Name :
Polarizability paramaters : Molar refractivirty ( MR)
The molar refractive is a measure of both the volume of a compound
MR = (n2 -1) M/ ( n2 +2)d
n – refractive index
M – Molecular weight
d – Density
Significance : Molar refractivity in QSAR equation – ligand – enzyme interaction.
Parachor : The parachor [P] is the molar volume V which has been
corrected for forces of inter molecular attraction by multiplying the fourth root of
surface tension γ = [P] = vγ1/4 = Mγ1/4/ D
M – molecular weight ; D – density ;

246
Topic Name :
Electronic parameter : The distribution of electron in a drug molecule has a
considerable influence on the distribution and activity of the drug. In general, Non –
polar and polar drug in their unionized form are more readily transported through
membranes than polar drugs and drugs in their inonized form. The first attempt to
quantify the electronic effect of groups on the physico chemical properties of
compound was made by Hammette.
The Hammett Constant (σ) : The distribution of electrons within a molecule
depends on the nature of the electron with drawing and electron doanting group
found in the structure. Let us study the substituted benzoic acids
electronic parameters in QSAR relationship Hammett constant are defined
as :
σ = log Kbx/Kb = σx = log K bx – log KB & so Pka = - log Ka

247
Topic Name : Hammett susbstitution constant (σ) is a measure of the electron
withdrawing or electron donating ability of a substituent and has been determined
by comparing the dissociation series of substituted acid with that of parent or
unsubstituted acid.
The values of σ for a particular substituent will depend on whether the
substituent is meta or para. It is used as a subscript m or p
Dis advantages : Hammett constant suffer from the disadvantage that they
only apply to substituents directly attached to benzene ring.

248
Topic Name : Inductive substituent constant : Hammette constant is a measure of
both inductive and mesomeric effect. The P- substituent constant (σp) has a
greater resonance component than the equivalent constant ( σm) and the
inductive contribution can be calculated from the inductive susbstituent constant
(σ1)
(σ1) = ½ ( 3σp-σm)
It is used in aliphatic compound in which influencing and influenced group
to form a part of a conjugated system.

249
Topic Name : Taft’s substituent Constant
Taft’s substituent constant ( σ*) are a measure of the polar effects of
substituent in aliphatic compound when the group does not part of a conjugated
system.
Suppose when a ester hydrolysis , it is calculated from the following
equation :
σ* = 1 / 2.48 [ log (k/k0)B – log (k/k0)A
Where K represents the rare constants for the hydrolysis of the substituted
constant.
K0 = methyl derivative
B – basic hydrolysis
A- Acid hydrolysis
2.48 – Hammett constant –
Taft’s constant – Methyl group is the standard for which the constant is
zero.
σ* = 2.51σ t

250
Topic Name : Hansch Analysis
This is the most popular mathematical approach to QSAR introduced by
Corwin Hansch
It is divided in to two stages : 1) Transport of drug to its site of action.
2) The binding of drug to the target site.
Hansch analysis are described by the parameters which correlate in the
biological activity.
The most commonly used physio chemical parameters for Hansch analysis
are log p, π,σ and steric parameters as practically all the parameters used in
Hansch analysis.So it is known as “ Linaer free enery approach” or extra
thermodynamic approach””
The hydrophobicity values are limited, the equation will be linear as follows :
log (1/c) = K1 log P + K2 σ+K3 E3+ K4

251
Topic Name : Hansch Analysis
where K1, K2 and K3 are constant obtained by least square procedure.
C – Molar concentration
The molecule which is too hydrophilic and too lipophilic which will not be
able to cross the lipophilic and hydrophilic barriers respectively.
log (1/C) = -K (log p)2 +K2 log p +K3σ+K1E6+K5
The constant K1-K5 are obtained by least square method. The extra
thermodynamic equation following rules are formulated by Hansch :
1. Selection of independent variables. A wide range of different parameters
like log p, π,σ,MR, steric parameters should be tried.
2. All the resonable parameters must be validated by appropriate
statistical procedure.
3. All the equations are equal than one should accept the simplest one.
4. Number of atoms or variable should be at least 5 or 6 data point per
variable to avoid chance co-relations.
5. Hansch model which is consistent with known physical organis and bio-
medical chemistry

252
Topic Name : Applications of Hansch Analysis
1. Hansch equation is used to predict the activity of unsynthesized
analogue.
2. Hansch analysis may also be used to give an indication of the
importance of the influence of parameters on the mechanism by which drug acts.
3. The accuracy of Hansch analysis equation depends on :
 The number of analogues (n) used .
 The higher the probability of obtaining an accurate hansch equation.
 The accuracy of biological data used in the derivative of the equation.
The choice of parameters

253
Topic Name : Craig plot

254
UNIT-5 –PHARMACOPHORE MODELING
Topic Name :Pharmacophore modeling :
1. Pharmacophore represents the molecules features such as : 3D
(Hydrophobic group, ionizable group, H – donor or acceptor)
2. 2D ( Sub structures)
3. ID ( Physical and biological properties)
Pharmacophore approaches have become one major tools in the drug discovery.
Various ligand based and structure based methods which have been developed
for improved pharmacophore.
Pharmacophore is used for virtual screening, de novo design and lead
optimization.

255
Topic Name :Pharmacophore modeling :

256
Topic Name :Pharmacophore based on drug :

257
Topic Name : Computer aided drug design.

258
UNIT-5 –DOCKING TECHNIQUES
Topic Name :Docking techniques
1. Docking is a method which predicts the preferred orientation of
one molecule to a second when bound to each other to form a stable complex.
2. The associations between biological relevant molecules such as proteins,
peptides, nucleic acids, carbohydrates and lipids play a role in signal induction.
3. Molecular docking is one of the most frequently used method in structure
based drug design
4. Molecular docking is the lock and key mechanism – Protein is a lock
5. Ligand is a key
6. the protein and ligand will kind conformation adjustment resulting in
overall biding is referred as “ Induced fit”

259
Topic Name : Docking approaches
1. two approaches are popular with in the molecular docking community.
2. The second approaches simulates the docking process in which ligand-
protein pair wise interaction energies.
3. there are two stages :
1. Shape complementarily
2. Simulation.
1. Shape complementarily : Geometric matching & shape complementarily
methods to describe the protein and ligand dockable.
2.Simulation : Simulation is a docking process, in which the protein and ligand are
seperated by some physical distance, and the ligand its position in to the proteins
active site after a certain numbe rof moves in conformational space.

260

261
UNIT-5 – Combinatorial chemistry
Topic Name : Combinatorial chemistry
 Combinatorial chemistry has its earliest orgin in solid phase peptide in 1960
by Bruce Merrifield.
Drug discovery is a lengthy and expensive process, with in which the
syntheis of exploratory compounds.
Combinatorial chemistry can be viewed as atool which allows large
number of compounds to be synthesized simultaneously in atime taken to prepare
a handful compounds by traditional synthetic methods.
Combinatorial synthesis is a simultaneous synthesis of large number of
possible compounds that could be formed from a number of building blocks. The
product is known as “Combinatorial library”

262
Topic Name : Difference between conventional synthesis and combinational
synthesis

263
Combinatorial chemistry can be applied to :
Solution Phase synthesis
Solid Phase synthesis
Solid Phase synthesis :
In this method, The reaction is carried out on a solid
support such as resin beads.
The bead is treated with different starting materials, which bound
together. Which is mixed with another reagent to get the product.
Large excess of reagent solvent can be used to drive the reaction
sequence.
The essential requirement for solid Phase synthesis are :
1. Cross linked insoluble ploymeric support which is inert to
synthetic conditions to resin.

264
2. Anchor or linker covalently linked to the resin.
3.Bond linking the substrate to the linker, which will be stable to the reaction
condition.
4.Chemical protecting groups for protecting the functional group not
involved in the synthesis.
1. The solid support : The solid support depends on the type of
reaction some of the examples are : Polystyrene ; Tentagel ; Pepsin : PEGA
2. Linkers : The linker is the molecule that sits between compound
and the solid support.

265
Resin having different linkers has different names :
1. The wang resin – It has linkers which is suitable for the
attachment and release of carboxylic acids.
2. The Ring Resin : Suitable for the attachment of carboxylic acid
and the release of carboxamide.
3. The dihydropyran derivative resin : suitable for the attachment of
alcohol.
4. Protecting groups : Protecting groups are important for blocking
and regenerating functional group in a reaction sequence.

266
Topic Name : Parallel synthesis

267
Topic Name : Parallel synthesis
In this method, the compounds are synthesized in separate vessel in a
parallel manner
The array of reaction vessel are taken either in a grid well in a plastic plate
which are called as crowns.
The structure of product formed is usually identified by the grid code.

268
Topic Name : Mix and split technique.

269
Topic Name : Mix and split technique.
Mix and split technique is used for to make both large and small
combinatorial libraries.
A both of resin is divided in to equal portion in different reaction vessel.
Each portion of resin is treated with different derivatives of the first building
block ( A, B &C).
After washing to remove the excess reagent and by products the beads
are pooled together in one pot and mixed thoroughly.
Thus the beads are split in to portion, mixed together and res plit upon the
number of different building blocks be used

270

271
Topic Name : De convolution : The compound mixture proves to be biologically
active. Isolation and identification of the most active compound in mixture is known
as deconvolution.
Encoding methods : Encoding methods use a code to indicate in the
synthesis and identify the structure of the library member. Two popular techniques :
1. Chemical tagging method
2. Radiofrequency tagging.
Chemical tagging method: Chemical tagging method uses specific compounds as
a code for the individual step for synthesis.
Radio frequency tagging : Tags are robust, encapsulated in glass casing, stable to
chemical and synthetic conditions.

272
Topic Name : Solution Phase synthesis
The main problem in combinatorial synthesis in solution can be used to
produce libraries. A combinatorial library of amides forming by reacting a set of five
acid chlorides ( A1- A5) with ten amines (B1- B10).
Each of the five acid chlorides is reacted separately with an equimolar
mixture of all ten amine and each of the amine is reacted with an equimolar
mixtures of all the acid chlorides.

273
UNIT-5 – Drug design &
Combinatorial chemistry
Reference Links :
• Book Details : Medicinal chemistry by K.Elnago
• Video Link Details
• Video Link details : https://www.youtube.com/watch?v=eXAe-rN3t0I ; https://www.youtube.com/watch?v=Sts6TDc-wz4
If avaliable :Drug design and QSAR Pharmacophore_ Modeling_ in_ Drug_ Discovery.pdf

274
Tutorial Problems :
MCQ's :
1. Which of the following lead compound?
a. A compound that contains element lead
b. A compound synthesized in the lab and go forward for preclinical
and clinical trials
c. The first compound reaches the market
d All of the above ans : b
2. What is meant by ADME ?
a. affinity, dosage, marketing, efficacy
b. absorption, distribution, metabolism, excretion
c. Agonism, dependence, mobility, efficiency
d. Anatognism, defiency, mean, efflux ans : b
:

275
Tutorial Problems :
MCQ's :
3. Solid Phase synthesis is frequently used in combinatorial
chemistry.What is meant by solid phase synthesis?
a.Reactions are carried out with solvent
b. Reagents and Reactants are attached to a solid phase support.
c. Reagents are used in solid phase.
d.Molecules are constructed on a solid phase support
Ans :b
4. Mix and split technique may be used for
a. Both large and small combinatorial libraries
b. Large combinatorial libraries
c. Small combinatorial libraries
d. All of the above
Ans :a

276
Tutorial Problems :
MCQ's :
5. Hansch equation is used to predict :
a. The activity of unsynthesized analogue
b.The activity of synthesized analogue
c. Both a & b
d. None of the above ans : a
6. Taft’s constant is used to measure :
a. The polar effects of substituent in aliphatic compound
b. The polar effects of substituent in aromatic compound
c.The polar effects of substituent in conjugated system
d. None of the above.
ans : a.

277
1. Explain the parameters in the QSAR studies?
2. Explain the hammett constant and its applications?
3. Write a note on Taft’s substituent constant?
4. Write a detailed note on Pharmacophore modeling and docking studies?
5. Explain the concept in hansch analysis and its applications?
6. Write a short notes on combinatorial synthesis and its applications?
7.Write a detailed note on solid phase and solution phase synthesis?

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