Medicinal chemistry III Unit no 1 -Antibiotics

ANTIBIOTICS IS DEFINED AS THE AGENT WHICH KILL OR INHIBIT GROWTH OF MICRORGANISM IN LOW CONCENTRATRION.Antibiotics are produced by various species of microorganism such as bacteria,fungi,.there are two types of antibiotics narrow spectrum antibiotics and broad spectrum antibiotics

1. a INTRODUCTION

The word Antibiotic has its origin from the word antibiosis ie against life
In present usage, the term Antibiotic includes chemically

related and derived substances. anti
Antibiotics are produced by various species of

microorganisms such as bacteria, fungi, and actinomycetes.

ANTIBIOTICS

Antibacterial drug Sy

Antifungal drug

Ania agent 990

Antiparasitic drug

+ Definition
Y Antibiotics
ntibiotics are chemic: stances produced by
ns, which in low concentration de:
th of other species of microorgani
Y” Chemotherapy
* Antibiotic therapy is also called chemotherapy which has come to
mean ‘Treatment of systemic infections with specific drugs that
selectively suppress/kill the infecting microorganism without
significantly affecting the host!

2. v Chemotherapeutic agent
Initially this term was restricted to synthetic compounds, but many
antibiotics and their analogues now synthesized poth synthetic and
microbiologically produced drugs. fa |
The term Antimicrobial agent NN
(AMA) to designate synthetic as ‘
well as naturally obtained drugs ER
that attenuate microorganisms.
v Narrow-Spectrum antibiotics & Broad-Spectrum antibiotics
> Narrow-spectrum antibiotics
* These are effective only against a few species of bacteria, gram-
positive or gram negative, fungi, or protozoa.
> Broad-spectrum antibiotics
* These antibiotics which are effective against a
variety of microorganisms, both gram-positive and

gram-negative bacteria
Y” Bactericidal and Bacteriostatic

Itreversibly inhibit the | It antibiotics kill the organisms

growth of susceptible | in vitro.

microorganisms,

/ Cross Resistance.

* The resistance of a
microorganism may be
natural (inherent or
intrinsic) or acquired.
Resistance may develop
during use of an antibiotic.

3. © Microorganism resistant to one antibiotic may become resistant to |
another and this is termed cross resistance.
History
“ Paul Ehrlich “The Father of Modern Chemotherapy’ coined the term
‘chemotherapy’
¥ The evolution of chemotherapy can be studied in three periods.
> Pre-Ehrlich era —before 1891
> The period of Paul Ehrlich
> Post-Ehrlich era — after 1935
¥ Domagkin 1935 demonstrated that Prontosil, a sulfonamide dye.

Alexander Fleming in 1928 observed the killing of staphylococci by a
fungus (Penicillium notatum)

+ Observed by others - never exploited

+ Florey & Chain purified it by freeze-drying (1940) - Nobel prize 1945
+ First used in a patient: 1942

+ World War II: penicillin saved 12-15% of lives

The history of chemotherapy may be divided into 3 phases |

1. The period of empirical use: —

ur
* Chinese invented a crude antibiotic from moldy SEL Ñ

soybeans curds and used it treat boils, pimples.

* Chenopodium by Aztecs for intestinal worms

* Chaulmoogra oil by the Hindus in leprosy.

* Mercury by Paracelsus (16th century) for syphilis,
+ Cinchona bark (17th century) for fevers. Paracelsus
Ehrlich’s phase of dyes and organometallic compounds
(1890-1935):-

* Ehrlich toyed with the idea that if certain dyes

in microbe:

could selectively st

they could also |
be selectively toxic to these organisms.

He tried methylene blue, trypan red, etc. PA

4. He developed the arsenicals—atoxyl for sleeping sickness
arsphenamine in 1906 and neo arsphenamine in 1909 for syphilis.
He coined the term ‘chemotherapy’ because he used drugs of known
chemical structure.

3. Modern era of Chemotherapy

* It was ushered by Domagk in 1935 by

demonstrating the therapeutic effect of

Prontosil, a sulfonamide dye, in pyogenic

infection.

It was soon realized that the active moiety

was para amino benzene sulfonamide,

and the dye part was not essential.
Sulphapyridine (M & B 693) was the first
sulfonamide to be marketed in 1938.

Some important years in history of antibiotics

Gerhard Domagk

Class of ¢

Sulphonamides Glycopeptides

Penicillins Rifamycins

Aminoglycosides Nitroimidazoles

Cephalosporins Quinolones

Chloramphenicol Trimethoprim

Tetracyclines Oxazolidinones

Macrolides / lincosamide
/ Streptogramins

Lipopeptides

5. «+ CLASSIFICATION
Antimicrobial drugs can be classified on the basis of many characteristics

cya es

Sulfonamides and | Sulfadiazine and others, Sulfones—Dapsone
related drugs (DDS), Paraaminosalicylic acid (PAS)
Diaminopyrimidines | Trimethoprim, Pyrimethamine.

PIE: Nalidixic acid, Norfloxacin, Ciprofloxacin,

Prulifloxacin, etc.

B-Lactam antibiotics

Penicillins, Cephalosporins, Monobactams,
Carbapenems.

Aminoglycosides

Tetracyclines Oxytetracycline, Doxycycline, etc.
Nitrobenzene derivative | Chloramphenicol |:
Streptomycin, Gentamicin, Amikacin,

Neomycin, etc.

Macrolide antibiotics

Erythromycin, Clarithromycin, Azithromycin,
etc.

Lincosamide antibiotics

Lincomycin, Clindamycin.

Glycopeptide antibiotics

Vancomycin, Teicoplanin

Oxazolidinone

Linezolid

Polypeptide antibiotics

Polymyxin-B, Colistin, Bacitracin, Tyrothricin

Nitrofuran derivatives

Nitrofurantoin, Furazolidone.

Nitroimidazoles

Metronidazole, Tinidazole

Nicotinic acid derivatives

Isoniazid, Pyrazinamide, Ethionamide

Polyene antibiotics

‘Nystatin, Amphotericin-B, Hamycin.

Azole derivatives

Miconazole, Clotrimazole, Ketoconazole,
Fluconazole

6. Penicillin
+ Cephalosporin

+ Griseofulvin

+ Polymyxin B
+ Colistin

* Bacitracin
+ Tyrothricin
* Aztreonam

Actinomycetes + Aminoglycosides

+ Chloramphenicol
+ Polyenes

* Macrolides

+ Tetracyclines

Antibacterial

TYPE OF ORGANISMS AGAINST WHICH

PRIMARILY ACTIVE

Penicillins, Aminoglycosides,
Fluoroquinolones, etc.

Erythromycin,

Antifungal | Griseofulvin, Amphotericin B, Ketoconazole, etc.
Antiviral | Acyclovir, Amantadine, Zidovudine, etc.
Antiprotozoal | Chloroquine, Pyrimethamine, Metronidazole, Diloxanide,
ete.
Anthelmintic | Mebendazole, Pyrantel, Nicosamide, Diethyl carbamazine,

etc.

7. NARROW-SPECTRUM | BROAD-SPECTRUM

Penicillin G Tetracyclines
Streptomycin Chloramphenicol
Erythromycin -

BACTERIOSTATIC El
Sulfonamides Penicillin's
Tetracyclines Aminoglycosides

Chloramphenicol Polypeptides
Erythromycin Isoniazid
Clindamycin Metronidazole

8. Drug that inhi

its cell

wall synthesis

B-lactam antibiotics (Penicillin, Cephalosporin,

Monobactams, Carbapenems) — Cycloserine,

Bacitracin, Vancomycin, Fosfomycin

Drugs affect

cell

membrane

Polypeptides (Polymyxins, Colistin,
Tyrothricin), Polyenes (Amphotericin B,
Nystatin, Hamycin), Azoles (Ketoconazole,

Fluconazole, Itraconazole)

protein

Drugs that inhibit

Tetracyclines, Chloramphenicol, Erythromycin,

Clindamycin, Linezolid

Drugs that alter

protein

synthesis by Misreading
of mRNA code

Aminoglycoside

Drugs that inhibits DNA
synthesis

Acyclovir, Zidovudine

function

Drugs that affect DNA

Rifampin, Metronidazole

9. Drugs that inhibit DNA Nalidixic acid and Fluoroquinolones
gyrase

Antimetabolites

Sulphonamide, Sulfones, PAS, Dapsone,
Trimethoprim, Pyrimethamine, Ethambutol

QUESTIONS FROM THE ABOVE TOPICS ]

Very short answer type questions [2 marks)

Short answer type A (4 marks)

Langan un (rm |

10. Q INTRODUCTION

“+ Mechanism of action

B-lactam antibiotics (beta-lactam antibiotics) are the antibiotic agents |
that contain a beta-lactam ring in their molecular structures.

Structure having a lactam group with a a 8
heteroatom structure consisting cyclic amide

with three carbon atoms and one nitrogen J #4
atom this ring named as Azetidinone. B- Lactam ring

B-lactam ring is much more reactive and more sensitive to nucleophilic
attack.

Bacteria often develops resistance to ß-lactam antibiotics by
synthesizing a B-lactamase, an enzyme that attacks the B-lactam ring.
To overcome this resistance, B-lactam antibiotics are often given with B-
lactamase inhibitors such as clavulanic acid.

The important groups includes penicillin derivatives (Penams),
Cephalosporins (Cephems), Monobactams and Carbapenems.

B-lactam mechanism
of action

ABK free
Cel Wail
Synthesis

fen ph no Ca skal
omoonesruimmen |] | | crossing a cet wot tess

11. The penicillin's cause the lysis of growing bacteria. They bind to the
enzymes involved in the biosynthesis of the bacterial cell wall

The penicillin's and the other B-lactam antibiotics have a structure that
closely resembles that of acylated D-alanyl-D-alanine.

Penicillin's bind to a number of receptor pación anibal

proteins transpeptida and =.
carboxypeptidases called penicillin binding +

proteins (PBPs), the enzymes that catalyze the niit crss-inung of pestdogycan
synthesis of peptidoglycan,

This leads to the interruption of cell wall
synthesis, consequently leading to bacterial cell

Coll wall defcientbactena

+
growth inhibition and cell lysis. Orge
Different microorganisms vary in the affinity of +
their PBPS for penicillin. Bactericidal eect |

o = |
Ue ss IH s
R-C-N =e |
pred Ke BL
N N
los a Lo x
Asyl Aci coo
group group
B-lactam + Thiazolidine lactam + Dihydrothiazine

Ry
fal ‘com
B-lactam + Pyrolidine

12. < Various B-lactam antibioti
1. Penicillin
2. Cephalosporin
3. Other B-lactam antibiotics.
a. B-lactamase inhibitor - Clavulanic acid, Sulbactam and
Tazobactam
b. Monobactam- Aztreonam
¢. Carbapenem- Imipenem

+ Conjugation with other ring-

5
ON Penam B- lactam ring + Thiazolidine ring
IN
o'
S.
"9 Cepham | f-lactamring +Dihydrothiazine ring
IN
o
p, Oxapenam B- lactam ring + Oxazolidine ring
qa
Carbapenem | _- lactam ring + Pyrolidine ring
o=|

+ Classification of B-Lactum drugs

Saturated five Unsaturated five
membered rings member ring

13. 1. Saturated five-membered rings
* Saturated five-membered rings contain f-Lactam ring fused with
saturated five membered rings and classified as Penams, Carbapenams
and Oxapenams.
* Penams having thiazolidine rings(penicillin)
* Carbapenams having pyrrolidine rings
Oxapenams having oxazolidine rings, where oxygen atom was
replaced by sulfur when compared with penam molecules.

R R R
8
ma] (>
N N N
o o o
Penam COOH) Carbapenam COOH) Oxapenam

2. Un-saturated five-membered rings
* The B-Lactam compounds with unsaturated five membered rings are

classified as Penems and Carbapenems.

Penems containing dihydrothiazole rings, faropenem belongs to this

category.

Carbapenems containing Dihydro- 1H-pyrrole rings

They are the last remedy for many bacterial infections,

R

3. Un-saturated six-membered rings
* Their examples are Cephems, Carbacephems and Oxacephems.

* In Cephems, &-Lactams are combined with 3, 6-dihydro-2H-1, 3-

thiazine ring.

All the Cephalosporin antibiotic compounds are come under this

category.

14. In Carbacephems, the Sulfur atom is substituted by Carbon atom in
Cephem moiety. This prevents bacterial cell division by inhibiting cell

4. B-Lactams not fused with any other rings

In these compounds, B-Lactam ring is not fused with any other rings.
Monobactams are come under this category of molecules.
Aztreonam and Tigemonam are examples of this category.

15. (INTRODUCTION ge

Penicillin was the first antibiotic to be used
clinically in 1941.
It is a miracle that the least toxic drug of its
kind was the first to be discovered.
Penicillin was originally obtained from the
fungus Penicillium notatum, but the present
source is a high yielding mutant of P
chrysogenum.
+ Chemistry and properties

* Natural Penicillin's are dextrorotatory.

Penicillium
chrysogenum

¥

* Aqueous penicillin G is drug of choice for neurosyphilis.

* Valine is the biosynthetic precursor for natural penicillin.

Historical Background

1 | 1928 | Alexander Fleming accidentally developed penicillin.

Florey and co workers isolated a compound by freeze
2 | 1930 | drying process from the fungus strain and named it
penicillin.

D. Hodgkin's elucidated the chemical structure of
penicillin.

3 | 1945

Sheehan develops synthetic route for production of

4 1957 las
penicillin

Beechams isolates 6 aminopenicillanic acid (6-APA) to
5 | 1958 | use as intermediate for semi-synthetic penicillin
derivatives.

16. lates natural product called, Clavulanic acid | |

6 | 1976 | that is effective in preventing enzymatic digestion of |

penicillin in resistant-strains of bacteria |
|

7 1959 British scientists reported the isolation of 6-APA from a
culture of P. chrysogenum |

Sheehan and Ferris converted a natural penicillin to an
intermediate, from which the acyl side chain has been |

8 | 1971
cleaved and which then can be treated to form biologically

active.

+ Nomenclature
Y Two numbering systems for the fused heterocyclic system exist.

1 Chemical Abstract

United states
pharmacopoeia (USP)

* According to Chemical abstract, penicillin's are numbered start from ‘S’
atom. Sulfur atom assigned as 1st position and N atom assigned as in the 4th
position and is called as 6- acylamino 2,2-dimethyl-3-carboxylic acid

* According to USP system, 'N' atom assigned as 1st position and 'S' atom

assigned in the 4th position and is called as 4-thia- 1-azabicyclo heptone

17. adopted for general use:

Ho’

Structure description
Penam * Itis used for unsubstituted bicyclic
Ss system, including the amide carbonyl
> group.
N + They are designated according to the
o Chemical Abstract system as 5-
acylamino-2,2-dimethylpenam-3-
carboxylic acid.
Penicillanic acid + Itis used to describe the ring system
E with substituent that are generally
HE ch present (i.e, 2,2-dimethyl and 3-
id carboxyl):

Itis Used to name the entire 6-
carbonylaminopenicillanic acid portion
of the molecule penicillin and then
distinguishes compounds on the basis of
the R-group of the acyl portion of the
molecule.

18. Three chiral carbon atoms i. e. C 1-Configuration

and C-6 are present in the penicillin
molecule.

All naturally occurring, synthetic and

o
1
semi-synthetic penicillin's possess the rh N „ch
same absolute configuration about E EOS,
these three centers for antimicrobi: oe
activity. HU,
The carbon atom bearing the
acylamino group (C-6) has the
L-configuration, whereas the carbon to which the carboxyl group is
attached has the D- configuration.
The acylamino and carboxyl groups are trans to each other, with the
former in the a and the later in the $ orientation relative to the penam
ring system.
The atoms composing the 6-aminopenicillanic acid portion of the
structure are derived biosynthetically from two amino acids, L-cysteine
(S-1, C5, C-6, C-7 and 6-amino) and L-valine (2,2-dimethyl, C-2, C-3, N-4
and 3-carboxyl).

0

To Nth
OS

The absolute stereochemistry
of the penicillin is designated
as 3S: 5R: 6R

+ Structure Activity Relationship

D-configuration

19. Chemical degradation of penicillin

The cis relationship between the two hydrogen:
free 3-carboxylate and a
ina loss of activity.

The side chain determines antibacterial spectrum and pharmacologic
properties.

The substitution of a side-chain 'R' group on the primary amine with an
electron withdrawing group decreases the electron density on the side-
chain carbonyl and protects these penicillin's.

The more lipophilic the side chain of penicillin, the more serum protein
bound to the antibiotic.

B-lactamase stability of penicillin increases, when the aromatic ring is
attached directly to the side-chain carbonyl and both ortho positions are
substituted by methoxy groups.

The dimethyl substitution at 2nd position is necessary for activity, if any

ide. Changing one or more of these results

other substitution or changes in this position decreases the activity.

—
ans |

Thiazolidine S-membered
saturated ring

Carbonyl oxygen Carboxylic group

The penicillin's are very reactive due to the strained amide bond in the |
fused B-lactum of the nucleus.
They are extremely susceptible to nucleophilic attack by water or |
hydroxide ion to form the penicilloic acid.

P-Lactamases also cleave the f-lactam ring to give penicilloic acid
with a loss of antibacterial activity.

20. al 5,
cH
NS Nes

Penicillin” ‘coon Hooc HN Sch
5

Penicilloic acid ‘coon

i=
ns—t—ch,

'=E-N—cHl,~cooH
toot gs
Hs” ‘cH
Penamaldie acid

S,

R—OC—HN—C A
AS

Penilloic acid ‘COOH

R—CONH + —cHo
Coon ||

Penaldic acid
Penieillamine

Penicillaldehyde bases

21. The deterioration of penicillin occurred due to reactivity
1 | (hydrolysis) of the strained lactam ring, influenced by the pH of
the solution.

B-lactam carbonyl group of penicillin undergoes nucleophilic
attack by water (-OH) to form the inactive penicilloic acid

Protonation of the B-lactam nitrogen, followed by nucleophil |
attack of the acyl oxygen atom on the B-lactam carbonyl carbon

Opening of the &-lactam ring destabilizes the thiazoline ring
which form the penicillanic acid.

Rearrangement of penicillanic | Hydrolysis of the oxazolone ring to
acid to a penillic acid form the unstable Penamaldic acid

Penillic acid decarboxylates and | Penamaldic acid easily hydrolyzes to
forms penilloic acid penicillamine and Penaldic acid

The third product of the degradation
is penicilloaldehyde formed by
decarboxylation of penaldic acid

Penicillin -V
(phenoxymethylpenicillin)

Acid resistant penicillin

Penicillinase resistant Methicillin , oxacillin,
penicillins cloxacillin, dicloxacillin

Extended spectrum penicillin

(a) | Aminopenicillin | Ampicillin, Amoxicillin , Bacampillin

22. 3 | Extended spectrum Penic
(0) | Carboxypenicillin Carbenicillin , Ticarcillin
(©) | Ureidopenicillin Piperacillin , Mezlocillin
(4) | Mecillinam Amdinocillin

| + Important products of Penicillin

1. Penicillin-G (Benzyl penicillin)
* PnG is a narrow spectrum antibiotic; activity is limited primarily to
gram-positive bacteria, few gram negative ones and anaerobes.

Acylamide

mel SOL js ‘Ka
2 CH

33-Dimethyl-7-ox0-6-(2-phenylacetamido) 0% 1 2 a
4-Tha--azabicyll3.20)

heptane Zearbosyicacd
api vol acid

-([-2-Amino-2-(4-hydroxyphenyl)
acetyljamino}

7-Oxo-4-thla-Lazableyelo[3.2.0]
ee |

Mi, o
|
On |
|
x
‘COOH

6-{{-2-Amino-2-(4-hydroxyphenyl) acetyl] amino)-3,3-dimethyl-7-oxo-4-thia-1
azabicyclo[3.2.0]heptane-2-carboxylic acid

23. | Re BEBE AS
Amoxicillin, like ampicillin, has a broad spectrum of use. |
Indications for use are the same as with ampicillin.

Synonyms of this drug are Amoxican, amoxil, larotid, robamox, trimox,
vimox, utimox, and others.

mthetic, narrow spectrum B-lactamase-resistant
penicillin antibiotic with bactericidal activity.

It is a 6-aminopenicillanic acid in which one of the amino hydrogens is
replaced by a 2,6-dimethoxybenzoyl group.
* Iris inactivated by gastric acid, so administered by injection.

Methiitin
6-[(26- dimethoxybenzosl)amino} 33-dimethy-7-oxo-4 tia
1-azabicyclo(3.2.0)heptane-2-carborylic acid.

4. Ampicillin

6-[-2-amino-2-phenylacety!]amino) -3,3-dimethyl-7-oxo-
4-thia-1-azabicyclo[3.2.0]heptane-2- carboxylic acid

Ampicillin is a white hygroscopic powder, freely soluble in water.

The corresponding product from acylation with 2-azido-4-

hydroxyphenyl acetyl chloride is amoxici

It is used to treat urinary tract infections and respiratory tract |

infections. |

i

24. Structures of some important penicillins

Ee hen

Pass

eg
a

ES Sc

LIRE
h g ‘COOH

cH, fy LA om
TER a EG 0-ch,-Û-NH ER“

Phenom pei

Oz Y oF th

Cook

vo Ampieillin

€ \ 1 5,
tE ane ot,
i

IN

00H

Nave

cap pranae tordo ( Da Piperacilin

ins OF x

+ Andi (in)

25. [ QUESTIONS FROM THE ABOVE TOPICS

Very short answer type questions (2 marks)

decomposition

nicillin

Short answer type questions (4 marks)

Long answer type questions (8 marks)

26. Q INTRODUCTION

* Cephalosporins are referred to as the ß-Lactam antibiotics, which are

among the oldest and frequently arranged of naturall
microbial agents

* The activity is similar to that of the penicillin's and

available anti-

these are coupled to penicillin binding protein
(PBPS) and interfere with cell wall enzymes.
+ These are isolated from Cephalosporium species
Historical background
* In 1945 with Giuseppe Brotzu's discovered that
cultures of C. acremonium inhibited the growth of a wide
variety of Gram-positive and Gram-negative bacteria.
* The development of antibiotic drugs was started after the
modification of 7-ACA side-chains with cephalothin as the
first drug inaugurated by Eli Lilly and company in 1964.

*% Nomenclature

C. acremonium

Cephalosporins consist of a four-membered lactam ring fused
through the nitrogen atom and the neighboring tetrahydral carbon
atom to a second heterocyclic ring forming a six-membered
dihydrothiazine ring.
Cephalosporins are named in the following ways:
1. Chemical abstracts:
5-Thia-1-azobicyclo (4.2.0) octanes. Accordingly, Cephalothin is 3-
(Acetoxymethyl)-8-oxo-7- (2-thienyl)
bicyelo[4.2.0]-oct-2ene-2-carboxylic acid.

acetamido-Sthia-1-aza-

27. 2. Cepham derivatives:
Cepham is the name given to the unsubstituted

bicyclic lactam. 07

Structure activity relationship

Replacement
00)

Substitution on 3)

The addition of amino group and a hydrogen to a
and al position produces basic compound

7-Acylamino _ | The phenyl ring in the side chain can be replaced
substitution | with other heterocycles with improved spectrum
of activity and pharmacokinetic properties.

Addition of methoxy oxime to a and al increases
the stability.

The benzoyl ester displayers improved gram-

positive activity.
Modification in

2. | the c-3 Displacement with aromatic thiols of 3-acetoxy
substitution | group results in an enhancement of activity
against gram-negative bacteria with improved
pharmacokinetic properties.

Other Methoxy group at C-7, shows higher resistance to
modifications | hydrolysis by B-lactamase.

28. Oxidation of ring spectrum to sulphoxide or
sulphone greatly destroys the antibacterial
activity,

Replacement of Sulphur with methylene group has
greater chemical stability and a longer half-life

Other
modifications

The antibacterial activity depends on the olefinic
linkage at C-3 and C-4 position and their activity is
lost due to the ionization of double bond to 2nd
and 3rd positions

* Chemical degradation of Cephalosporin

* Cephalosporins experience a variety of chemical and enzymatic
transformations, whose specific nature depends on the side-chain at C
7 and the substituent on C-3- atom.

A. In Strong Acid Solutions

CET HO R—C-HN Lactonise acid ar |
—
HR HOH Lctane (nae)
‘00H d

Desacetyl cephalosporin

B. In the Presence of acylase

On enzymatic degradation cephalosporin C gives 7-amino
cephalosporanic acid, which in the presence of acid undergoes

lactonization to give inactive lactone |

a Acylase LUE uN
[cephalosporin |
Pooper o CES
o
6

TACA

Dosacetyl-7-ACA lactone
(inactivo)

29. C. Inthe Presence of ß- lactamase

CHR,

coo#
Cephalospori Cephalosporie acid

Fragmentation and rearrangement

/ product(inactive)

Hy
doom anhydrodesacety cephalosporie acid

Hooc:

Enzyme ß-lactamase degraded cephalosporin C into cephalosporoic acid,
anhydrodesacetyl cephalosporoic acid, which leads to inactive products
+ Classification of Cephalosporin

* The most widely used system of classification of cephalosporins is by
generations and is based on the general features of their antibacterial
activity.
Cefalotin was one of the first cephalosporins to become available and is
representative of the first-generation cephalosporins.

First Second
generation generation

Cephalosporin's
fication

Third Fourth

generation generation

30. + (Parenteral)- Cefazolin

LEÍ . (oral)- Cephalexin, Cefadroxil

+ (Parenteral)- cefuroxime,

DUT à (Oral). cefacior, cefuroxime Axetil, Cefprozil

+ (Parenteral)- cefotaxime, ceftriaxone , Cefoperazone,
ceftazidime
+ (Oral)- cefixime, cefpodoxime Proxetil, cefdinir

+ (Parenteral)- Cefepime , Cefpirome

+ (Parenteral)- Ceftaroline Fosamil , Ceftobiprole Medocaril

+ Important products
1. First generation cephalosporins
a. Cephalexin
* Itisaß-lactam, first-generation Cephalosporin antibiotic with
bactericidal activity.
The a-amino group of cephalexin renders it acid stable and 3-methyl
group is responsible for the metabolic stability.

coon

Cephatexin

7-[amino-2-phenylacetyl]amino]-3-methyl-8-ox0-5
thia-1-azabicyclo[4.2.0]oct-

31. b. Cefadroxil

* Itisasemi-synthetic first-generation Cephalosporin with
antibacterial activity.

+ Itisa cephalosporin bearing methyl and (2R)-2-amino-2-(4-
hydroxyphenyl) acetamido groups at positions 3 and 7, respectively,
of the cephem skeleton.

* Ithas some immunostimulant properties mediated through T-cell
activation and that this is of material assistance to patients in fighting
infections.

ñ
w—/ ata s.
Ni
N
de iG a
Cefadroxil
Cook

7-(2-Amino-2-(A-hydroxyphenylJacetamido)-3-
methyl-8-0xo-5-thia-1-aza-bicyclo[4.2.0].
oct-2-ene-2-carboxylle acid

2. Second generation cephalosporins
a. Cefaclor
* Cefaclor is an orally active semi-synthetic Cephalosporin.
* It is a cephalosporin bearing chloro and (R)-2-amino-2-
phenylacetamido groups at positions 3 and 7, respectively, of the
cephem skeleton.

HO, 0
0
x
o
a A AO
— Cofactor las E
(6R,7R)-7-([(2R)-2-amino-2-phenylacety!]amino)-

3-chloro-8-0xo-5-thla-1-azableyclo[4.2.0]oct-2-ene- 2-carboxylic acid

* Cefaclor is used as an antibacterial drug and a drug allergen.

32. b. Cefuroxime

(6R,7R)-3-{[(Aminocarbonyl)oxy]methyl}-7-{{(2Z)~
2-(methoxyimino)acetyi]amino)-8-ox0-S-thla-1-azablcyelo[4.2.0]oct

2-furyl)-
-ene-2-carboxylle acid

* Cefuroxime axetil is a second-generation semi-synthetic Cephalosporin
* Itinhibits bacterial wall synthesis by a mechanism of action similar to
Cephalosporin
3. Third generation cephalosporins
a. Cefotaxime Sodium

CH;-Co0CH;
CooH

3-(Aceroxymethy)-7-(2-(2-aminothiazol-
acotamido) 8-0x0-5-thla-1-azabieyelo[4.2.0]oct-

-l)-2-(methoxyimino)

carboxylic acid
Cefotaxime sodium exists as white solid and soluble in water, exhibits
broad-spectrum activity against both gram-positive and gram-
negative bacteria.

* Used in genitourinary infection and lower respiratory infection.
b. Ceftazidime

* Ceftazidime is a third-generation, semi-synthetic, broad-spectrum

Cephalosporin antibiotic.
* Used especially for Pseudomonas and other Gram-negative |
infections »

Itis noted for its anti-pseudomonal activity AT

33. 7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetami
do)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-
bicyclo[4.2.0]oct-2-ene-2-carboxylate
4. Fourth generation cephalosporins
a. Cefepime

Cefepime

7-(2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-
3-((1-methylpyrrolidinium-1-yl)methyl)-8-ox0-5-thia-

1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

Cefepime is a fourth-generation Cephalosporin antibiotic developed in |

1994.

Itis active against Gram-positive and Gram-negative bacteria.

Used to treat severe nosocomial pneumonia, infection caused by multi

resistant micro-organisms.

5. Fifth generation cephalosporins

a. Ceftobiprole

Ceftobiprole is highly useful in treatment of hospital-acquire:
pneumonia and community-acquired pneumonia

Wy

34. DT

en]
As
7-{{(22)-2-(5-amino-1,2,4-thiadiazol-3-ylidene)- 2-nitroso-1-oxoethylJamino]-

8-0x0-3-[(E)-[2-0x0-1-[(3R)- 3-pyrrolidinyl]-3-pyrrolidinylidene]methyi]-5-
thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

QUESTIONS FROM THE ABOVE TOPICS

| Very short answer type ‘questions (2 marks)
|
|

Ceftobiprote yw

Short answer type questions (4 marks)

Long answer type questions (8 marks)

35. Q INTRODUCTION
* Beta-lactamases are a family of

‘enzymes involved in bacterial

resistance to beta-lactam

antibiotics.

They act by breaking the beta-

lactam ring that allows

penicillin-like antibiotics to

work.

To avoid this type of resistance

have developed the new beta-lactam antibiotics that are more resistant
to cleavage and the development of the class of enzyme inhibitors
called Beta-lactamase inhibitors.

Beta-lactamase inhibitors inactivate these enzymes and, in association
with beta-lactamase, provides wide spectrum bactericidal action

Classification of B-lactamase inhibitors
Itis divided into two classes :
> B-lactamase inhibitors with a B-lactam core:
* Tebipenem is the first Carbapenem to be
administered orally in the form of
Tebipenem-pivoxil. Structural and kinetic
studies of Tebipenem is available with M.
tuberculosis beta-lactamase (B-laC).
Clavulanic acid or clavulanate usually combined With
Amoxicillin or Ticarcillin.
Sulbactam, usually combined with ampicillin or Cefoperazone,
Tazobactam, usually combined with Piperacillin
rss
A am per vl

36. tors without a ß-

* Avibactam, approved in combination

with Ceftazidime , currently

undergoing clinical trials for

combination with Ceftaroline Zavicofta” 2 g/0.5 g*
* Relebactam, used in combination with phare)

Imipenem /Cilastatin en, i:

Vaborbactam, used in combination
with Meropenem.

+ Structure activity relationship

H,C—OH

‘COOH

* All the f-Lactamase Inhibitors should essentially contain ß- Lactam
ring (tetra cyclic amide)

* Any modification in ß- Lactam ring result in inactive compound

* Removal or substitution of hetero nitrogen atom by any other hetero
atom result in inactive compound.

* Removal of C-0 bond result in new compound with reduced activity.

® B-Lactamase inhibitors should irreversibly bind with enzyme and
inactive it. The rate and extent of formation of enzyme -inhibitor
complex determine the potency.

Important products of B-lactamase inhibitors

1. Clavulanic acid

O _CH—CH,—OH

_/%
4.(2-Hyaroxyethylidene)7-ox0
N
oe 3-(2-Hydroxyethyl

COOH | aza-bicyclo[3.2.0] heptane-2-carboxylic
acid

4-0xa-1-aza-bleyclo(3.2.0]
heptane-2-carboxyle acid

37. * Clavulanic acid is a semi-synthetic ß-lactamase
inhibitor isolated from Streptomyces clavuligerus.
* It acts as a suicide inhibitor of bacterial B-

lactamase enzymes. =
* Clavulanic acid is used in conjunction with ß- |
lactamase susceptible antibiotics, such as | |,
penicillin's and cephalosporins, to treat infections
caused by ß-lactamase producing organisms.
Einbomen

3,3-Dimethy!-7-0x0

VP CH,
oy?
CH;
N 2.Carbonylie acid
\ ‘COOH 3,3-Dimethyl-7-oxo-4-thia-1-
Mn Seem as azabicyclo[3.2.0]heptane-2-carboxylic acid
° 4,4-dioxide

* Sulbactam is a semi-synthetic B-lactamase inhibitor.

* Sulbactam, with a $ -lactamase susceptible antibiotic, such as penicillin's
or a cephalosporin, is used to treat infections caused by B-lactamase
producing organisms.

3. Tazobactum

3-Methyl-7-0xo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-
‘Tazobactum thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
4,4-dioxide

* This drug is used in conjunction with f-lactamase susceptible
penicillin's to treat infections caused by f-lactamase producing
organisms.

38. Q INTRODUCTION
* Fermentation of unusual microorganisms led to the discovery of
a class of monocyclic B-lactam antibiotics, named monobactams.
* The discovery of this class of antibiotics was first reported by —,
Skyes and Co-workers.
* The antibiotic was obtained from the _ bacterium
Chromobacterium violaceum.

They are part of B-lactam compounds but
unlike most other B-lactams, the B -lactam
ring of monobactams stand alone and is
not fused to another ring.

The monobactams are not effective against

Gram-positive bacteria or anaerobes. They
are used as injectables and inhalers.

“+ Mechanism of action
+ Monobactams work only
against aerobic gram- |
negative bacteria (Neisseri -
a, Pseudomonas).

Monobactams work
peptidoglycan synthesis process (a process essential to
maintain bacterial cell wall integrity)

* As a result, the bacteria lose the ability to resist and burst, leading to |
cell death. |

39. + Important products of Monobactams
1. Aztreonam
* It is an atypical B-lactam antibiotic in which the other ring is
missing , but acts by binding to specific PBPs

* It is narrow spectrum of action, isolated from Chromobacterium
violaceum.
Itinhibits gram-negative enteric bacilli and H. influenzae at very low
concentrations and Pseudomonas at moderate concentrations
Itis resistant to gram-negative ß-lactamases.
The main indications of aztreonam are hospital-acquired infections
originating from urinary, biliary, gastrointestinal and female
genital tracts.
> Structure of Aztreonam

[1-(2-Amino-1, , N
3-thiazol-4-yl)

=
‘=o 2-Oxoethylidene]
amino}
CH

Oxy-2-methyl
propanolc acid

Nso;H

-{[-2-Methyl-4-0x0-1-

sulfoazetidin-3-yljamino}
{[2-methyl-4-oxo-1-sulfoazetidin-3-
ino}oxy-2-methylpropanoic acid

40. 2. Tigemonam

2-{[1-(2-Amino-1,3-thiazol-4-yl)- 2-[[2,2-dimethyl-4-oxo-1-
sulfooxyazetidin-3-ylJamino]-2- oxoethylideneJaminoJoxyacetic acid

* Tigemonam is an orally administered monobactam.
* Tigemonam was more active than cephalexin and amoxi

clavulanate

QUESTIONS FROM THE ABOVE TOPICS

Very Short answer type questions (2 mar
What are monobactams ?
Explain the mechanism of action of Monobactams.
Give the general structure of Monobactams.

Short answer type questions (4

Explain the important products of Monobactams.

41. AMINOGLYCOSIDES |
Q INTRODUCTION
* These are a group of natural and semisynthetic antibiotics having
polybasic amino groups linked glycosidically to two or more
aminosugar (streptidine, 2-deoxy streptamine, garosamine) residues.

* These agents have broad antimicrobial spectra but their WR

use becomes limited because of its toxicity. ated .
SErs

* They have greater activity against gram-negative than
‘=

gram-positive bacteria
| + Historical backgrı

* Aminoglycoside antibiotics were the first drugs discovered by
systematic screening of natural product sources for
antibacterial activity.

* The laboratory of Waksman reported the discovery and isolation of the
aminoglycoside antibiotic streptomycin from soil bacteria in 194 |
was the first antibiotic effective against Mycobacterium
tuberculosis. #

Pan

The aminoglycosides are antibiotics, which may be described in

Mechanism of A

two main steps:

((A) Transport of the Binding hen

aminoglycoside through the

hibition of protein
bacterial cell wall and I

42. ® They act directly on the bacterial ribosome to inhibit the ini ion of |
protein synthesis and to interfere with the translation of the genetic |

message.

* They bind to the 16S rRNA portion of the 305 ribosomal subunit to
form a complex that cannot initiate proper amino acid polymerization |
and thus impairing function of the ribosome.

* The binding of streptomycin and other aminoglycosides to ribosomes also

causes misreading mutations of the genetic code.

ra
A y Blocks ination
ne

aie 5 go cite
5-9 —-s" translation and obits
@ prematuro termination
Drecton of
ANA wandten
ae ay emporio a
> incorrect amino acid

sanos |

i
Nee vow) OE
Neiimiein Injection A !
[nc 25)

Y be À
le

+ Chemistry of Aminoglycoside Antibiotics
* The aminoglycoside antibiotic term as aminoglycoside-aminocyclitols.

* They are incorporate amino-sugar with six-membered
aminocyclitorings, cyclic carbon ring functionalized with amino and

hydroxyl group.
EPA saga

Cyclic amino)
sugar

43. + Sources of drugs

Aminoglycosides are classified as broad-spectrum antibiotics, this are
use to treatment of serious systemic infections caused by aerobic
Gram-negative bacilli.

They are polycationic compounds that contain an aminocyclitol, with
Cyclic amino-sugars attached by glycosidic linkages.

‘Amino sugar portion

1 Streptomycin Streptomyces griseous
2 Neomycin S. fradiae
3 | — Kanamycin S. kanamyeleticus, S. kanamyceticus
4 | —Gentamycin Micromonospora purpura
5 Netilmicin Micromonospora species
6 | Tobramycin
s.

(Nebramycin) tenebrarius
7 | Framyce =

(Soframycin) Steals
8 Paromomycin ‘S.rimosus and S. paramomycinus
9 lan Ttis 1-L-(-) 4-amino-2-hydroxy butyryl ||

lana kanamycin

The aminoglycoside — antibiotics
contain two important structural
features. They are amino sugar
portion and centrally placed hexose
ring, which is either 2-
deoxystreptamine or streptidine.

Amino sugar portion

44. The bacterial inactivating enzymes targets C-6 and

C-2 position, and the substitution with methyl
Amino sugar | group at C-6 increases the enzyme resistance

portion

Cleavage of 3-hydroxyl or the 4-hydroxyl or both
groups does not affect the activity.

Amino sugar”
NH}

Ho 7
‚Amino sugar

Centrally placed hexose ring (aminocyclito ring)

The acylation (e.g. Amikacin) and Ethylation (e.g. 1-
N-ethylsisomycin) though does not increase the

Amino — | activity helps to retain the antibacterial potency.

cyclitol ring | 2-hydroxylation and 5-deoxygenation result in the
increased inhibition of bacterial inactivating enzyme

systems(Sisomicin series)

+ Classification of Aminoglycosides

45. Tobramycin
Amikacin

Sisomicin

Netilmicin

El =

Important products of aminoglycosides

. il 2.[-4-Amino-3,5-dihydroxy-
1. Amikacin mino arar CHZOH

4-Amino 2 hydroxybutanamido
on ©

ea ala
HaNH,CHC 2G <C-HN,

NS-Amino-ory
3-hydroxy-cyclohexyl CH,OH
6 |
HN 10
OH
2
4-Amino-N-[ -5-amino-2-[-4-amino-3,5-dihydroxy 6- A

(hydroxymethyl)oxan-2-yl]oxy-4-[ -6(aminomethyl)- OH OH

3,4,5-trihydroxy-oxan-2-yl] oxy-3-hydroxy- E Errar
cyclohexyl]-2-hydroxybutanamide Ad

46. * Amikacin is a semisynthetic drug derived form kanamyci

* Itretains 50% of the original activity of kanamycin A. ! æ
L-Isomer is more active than D-isomer. —

It resists attack by most bacterial inactivating enzyme.

Y” Dosage forms:

Amikacin sulphate injection LP.
2. Netilmicin (1-N-ethylsisomicin)

* Netilimycin sulphate is a white or yellowish-white hygroscopic
powder, very soluble in water, practically insoluble in acetone and
alcohol.

* It is useful for the treatment of serious infections due to susceptible
enterobacteria and other aerobic gram-negative bacilli
S-methyl-4-(methylamino) — 3-([-3-amino-6-(aminomethy])-
oxane-3,5-dlol pyran-2-yl]

HN 3s

Xo
H2C—NH,

NH,

H3C—CH)
4-Amino-6-(ethylamino)-2-
hydroxycyclohexyl]oxy}

2-{[-4-Amino-3-([-3-amino-6-(aminomethyl)-2H-pyran-2-yl] oxy)-
6-(ethylamino)-2 hydroxycyclohexyl] oxy}-5-methyl-4
{methylamino)oxane-3,5-diol

Assay:

* Itis assayed by microbiological method.

47. 3. Tobramycin

4-Amino-6-(hydroxymethyl) 3+{[-3-Amino-6-(aminomethyl)-

oxane-3,5-diol S-hydroxyoxan-2-yl]oxy)-

pa HN, ol
HOW CH, 2

x NH
Hy on CH;

OH Er
HN NH,

4.6-Diamino-2-hydroxy
eyclohexylloxy

4-amino-2-([ -4,6-diamino-3-{[-3-amino-6-(aminomethyl)-5-
hydroxyoxan-2-y!]oxy) -2-hydroxycyclohexyl]oxy} -6-
Chydroxymethyl)oxane-3,5-diol

Properties and uses:
* Its activity is similar to gentamycin. The superior activity of tobramycin
against P. aeruginosa may make it useful in the treatment of bacterial |

osteomyelitis, and pneumonia caused by P species. ©

amer
Dosage forms: | a
© Tobramycin injection LP. pas |
4, Gentamycin ==
5-Methyl-4-(methylamino)
oxane-3,S-diol 3-amino-6[-1-(methyl
‘amino}ethy!

HN NH

46-Diamino-Z-hydroxy
cyclohexylloxy}

48. Gentamycin C, CH, NHCH, H
Gentamycin C,, H NH H
Gentamycin C, CH, NH, H
Gentamycin C, H NH, CH,

* Gentamycin is a mixture of C,, Cz, and Cy, compounds, obtained
commercially from Micromonospora purpurea

+ Gentamycin sulphate exists as white hygroscopic powder, soluble
in water, and practically insoluble in alcohol, although it is a
broad-spectrum antibiotic.

QUESTIONS FROM THE ABOVE TOPICS

(2 marks) |

swer type qu

ry short

(4 marks)

z answer type questions (8 marks)

* Streptomycin is an aminoglycoside
antibacterial and antimycobacterial
© It is biosynthesized by Streptomyces griseus.

49. © streptomycin is an amino cyclitol glycoside that consists of Streptidine
having a disaccharyl moiety attached at the 4-position.

* It acts as a Triacidic base through the effect of its two strongly basic
guanidino groups and the more weakly basic methylamino group.

+ Structure
Han, NH
5-(2,4+-Diguanidino-3,5,6-
trihydroxy-yclohexory)
Ho. NH on
3
5 Streptidine
HA YA ° |
une 10,9 0H |
HC 5
SA CHOT” ony-3-nydroxy-2-metbyt
|, -tetrahydrofuran-3-carbaldehyde
L-Streptose
no, HO o
CH, 4-14,5-Dihydroxy-6-(tydroxymethy!
“y 3-methylamino-tetrahydropyran-2-yi]
HO OH. \NHCH; N-methyl-L-Glucosamine

Physical properties
* Streptomycin sulphate is a white hygroscopic powder, very soluble in |
water, and practically insoluble in ethanol.

Streptomycin sulphate
++ Factors that limit the therapeutic use of Streptomycin are- |
(1) Early development of resistant strains of bacteria. ?
(2) Neurotoxic reactions characterized by vertigo, hi “ a
disturbance of equilibrium and diminished
auditory perception.

50. „the possible development of damage to the optic nerve by

ay

(3) Ototoxicit
the continued use of streptomyein.
(4) Nephrotoxicity, need frequent
checks of renal monitoring
parameters. For systemic

action, streptomycin usually is

| given by intramuscular

injection

Uses

| + Streptomycin is active against numerous Gram-negative and Gram-
positive bacteria's.

* It is a broad spectrum aminoglycoside antibiotic used in treatment of
active tuberculosis, always in combination with other antituberculosis

| agents.

| © Itis used in eye infections

|

E ABOVE TOPICS

short answer type questions (2 marks)
Give the Structure of Streptomycin.
From which compound, Streptomycin is obtained ?
Short answer type questions (4 marks)
What are the factors that limit the use of streptomycin ?

Long answer type questions (8 marks)
Write a Note on streptomycin along with their uses.

Q INTRODUCTION
* Neomycin is isolated from Streptomyces fradiae.
* Neomycin is a broad spectrum aminoglycoside antibiotic and PARE!
shows a low incidence of toxic and hypersensitivity reactions Wag

51. + Structure
| 3,5-dlamino-6-hydroxy |
| tetrahydro-2H-pyran-3,4-diol cyclohexyloxy

CH,NH, NH, Deoxystreptamine |

Neosamine B

3
NH, 3-amino-6-(aminomethyl)-

4-hydroxy-2-(hydroxymethyl)— #5-dihydroxytetrahydro-
tetrahydrofuran-3-yloxy) 2H-pyran-2-yloxy)

* Neomycin isa mixture of three components

Neomycin B (Framycetin).
Neomycin B is composed of four
linked parts: D-neosamine, 2-
deoxystreptamine (2 - DOS) D-

ribose, and L-neosamine

Epimer
Neomycin
La

Neomycin Aisa
disaccharide, also
called Neamine,
contains D-neosamine
and2-
deoxystreptamine

Uses

+ Neomycin considered one of the most useful antibiotics for the treatment
of gastrointestinal infections, dermatological infections, and acute
bacterial peritonitis,

+ Itis used in abdominal surgery to reduce infections from bacterial flora

of the bowel. Good bacterial ora

090 sy

52. QUESTIONS FROM THE ABOVE TOPICS

ure of Neomycin.

h 3 compounds constitute the Ned

1. Write a short note on Neomycin

Q INTRODUCTION
* Kanamycin is an aminoglycoside bactericidal antibiotic isolated from the
bacterium Streptomyces kanamyceticus. Sard
Structure Sve
* The mixture consists of three related structures, that B
is, Kanamycin A, B, and C.
* The kanamycins do not possess D-ribose molecule
that is present in neomycins and paramomycins.

CHR

Kanamycin A = R,= NH, ; R¿= OH

Kanamycin B =R,=R¿= NH,
Kanamycin C =R;=0H; Rz= NH,

53. erties
* Kanamycin Sulfate is white, odourless crystalline powder.
* It has a potency equivalent to not less than 750 micrograms of kanamycin
per mg, calculated on the dried basis.
soluble in water; insoluble in acetone, in ethyl acetate, and in
benzene. pH of a 1% solution in water is between 6.5 and 8.5
* Store in airtight containers.
Uses:
1.Kanamycin is useful drug in the treatment of following conditions

Respiratory tract infections
AN Urinary tract infections

Blood, bone infections

Soft tissue infections

2. Kanamycin is useful drug in the treatment against following bacteria and

their infections
Enterobacter aerogenes
Klebsiella pneumoniae

Serratia marcescens

Acinetobacter species

QUESTIONS FROM THE ABOVE TOPICS |

‘Short answer type questions (4 marks)

Long answer type questions (8 marks)

54. u dl [AMINOGLYCOSIDES]

Q INTRODUCTION
* These are a group of natural and semisynthetic antibiotics having
polybasic amino groups linked glycosidically to two or more

aminosugar (streptidine, 2-deoxy streptamine, garosamine) residues.

+ These agents have broad antimicrobial spectra but their age

use becomes limited because of its toxicity. = e =
* They have greater activity against gram-negative than [E mew
gram-positive bacteria Ez y

+ Historical bac

Aminoglycoside antibiotics were the first drugs discovered by
systematic screening of natural product sources for
antibacterial activity.

* The laboratory of Waksman reported the discovery and isolation ofthe |
aminoglycoside antibiotic streptomycin from soil bacteria in 19.
was the first antibiotic effective against Mycobacterium

tuberculosis. 4
a SS |
The aminoglycosides are antibiotics, which may be described in|

two main steps:

{(A) Transport of the (B) Binding to ribosom
aminoglycoside through the

; pa phibition of protein
bacterial cell wall and

ytoplasmic membran

55. gg |

* They act directly on the bacterial ribosome to inhibit the initiation of
protein synthesis and to interfere with the translation of the genetic
message.

* They bind to the 16S rRNA portion of the 30S ribosomal subunit to |
form a complex that cannot initiate proper amino acid polymerization
and thus impairing function of the ribosome.

* The binding of streptomycin and other aminoglycosides to ribosomes also
causes misreading mutations of the genetic code.

Mature qa
y Blocks ination
Growing op © Fa Col)

B Blocks further
s o! translation and elicits

& _ premature termination
Diocten ei, '® |
ANA vanalaton 6

aminoglycosida p. neomostlon of

ee Injection LP E!
um k

+ Chemistry of Aminoglycoside Antibiotics
* The aminoglycoside antibiotic term as aminoglycoside-aminocyclitols. |
* They are incorporate amino-sugar with —_ six-membered |
aminocyclitorings, cyclic carbon ring functionalized with amino and

hydroxyl group. |
ES amino Le "pre Cycle amino
OR ih aes |

ta NH,

“U
Aminocyclitol ring

56. ssified as broad-spectrum antibiotics, this are

Aminoglycosides are cl

use to treatment of serious systemic infec

ons caused by aerobic

Gram-negative bacilli
They are polycationie compounds that contain

inocyclitol, with
Cyclic amino-sugars attached by glycosidic linkages,

H,
PS halal
Amino sugar por
Sources of drugs
1 | Streptomycin Streptomyces griseous
2 Neomycin S.fradiae
3 | Kanamycin S.kanamyeleticus, 5. kanamyceticus
4 | Gentamycin Micromonospora purpura
5 | —Netilmicin Micromonospora species
6 Tobramycin y
S. tenebı
(Nebramycin) enehrartus
7 | Framycetin -
(Soframycin) Salers
8 | Paromomycin 5. rimosus and S. paramomycinus
9 FE Itis 1-L-() 4-amino-2-hydroxy butyryl
IR e kanamycin

The aminoglycoside — antibiotics
contain two important structural
features. They are amino sugar
portion and centrally placed hexose NH
ring, which is either 2-
deoxystreptamine or streptidine.

Amino sugar portion

57. Amino sugar
portion

The bacterial inactivating enzymes targets C-6 and
C-2 position, and the substitution with methyl

group at C-6 increases the enzyme resistance

Cleavage of 3-hydroxyl or the 4-hydroxyl or both
groups does not affect the activity.

Amino suga/

fy
HO’ 3 4
Amino sugar

Centrally placed hexose ring (aminocyclitol ring)

Amino

The acylation (e.g. Amikacin) and Ethylation (e.g. 1-
N-ethylsisomycin) though does not increase the
activity helps to retain the antibacterial potency.

cyclitol ring

2-hydroxylation and 5-deoxygenation result in the
increased inhibition of bacterial inactivating enzyme
systems(Sisomicin series)

+ Classification of Aminoglycosides

58. _ Streptomyein |
Gentamiein Framycetin
Kanamycin
Tobramycin

Amikacin

Sisomicin

Netilmicin

+ Important products of aminoglycosides
A il i 2-[-4-Amino-3,5-dihydroxy-
1. Amikacin o y CHZOH
Amine 2hydronybutanamide
oH 0

4,3 al a
H2NHCHC— (CHN

N-S-Amino-oxy
3 hydroxy-cyelohexyl

HN

4-Amino-N-[ -5-amino-2-[-4-amino-3,5-dihydroxy 6-
(hydroxymethyl)oxan-2-yl]oxy-4-[ -6(aminomethyl)- OH OH
ri -oxan-2-yl] oxy-3- 2 ‘4{-6-(Aminomethy)-
3,4,Setrihydroxy-oxan-2-yl] oxy-3-hydroxy- Perra
cyclohexyl]-2-hydroxybutanamide

59. v

Amikacin is a semisynthetic drug derived form kanamyci
It retains 50% of the original activity of kanamycin A. =
L-Isomer is more active than D-isomer.

It resists attack by most bacterial inactivating enzyme.

Dosage forms:

Amikacin sulphate injection LP.

2. Netilmicin (1-N-ethylsisomicin)

Netilimycin sulphate is a white or yellowish-white hygroscopic
powder, very soluble in water, practically insoluble in acetone and
alcohol.

It is useful for the treatment of serious infections due to susceptible
enterobacteria and other aerobic gram-negative bacilli

S-methyl-4-(methylamino) — 3-([-3-amino-6-(aminomethyl)-
oxane-3,5-dlol pyran-2-yl]

HN 4 5

H¿C—NHz

E
H¿C—CH)

4-Amino-6-(ethylamino)-2-
hydroxycyclohexyl]oxy)

2-{[-4-Amino-3-{[-3-amino-6-(aminomethyl)-2H-pyran-2-yl] oxy)-
6-(ethylamino)-2 hydroxycyclohexyl] oxy}-5-methyl-4
(methylamino)oxane-3,5-diol

Assay:

* It is assayed by microbiological method.

60. 'obramycin |
4Amino6-(hydrowymethyt) 3

5

NH,

4.6-Dlamino-2-hydroxy
Ieohexyiloxy

4-amino-2-([ -4,6-diamino-3-{[-3-amino-6-(aminomethyl)-5-
| hydroxyoxan-2-ylJoxy} -2-hydroxycyclohexyl]oxy) -6-
(hydroxymethyl) oxane-3,5-diol

Properties and uses:
* Its activity is similar to gentamycin. The superior activity of tobramycin
against P. aeruginosa may make it useful in the treatment of bacterial

osteomyelitis, and pneumonia caused by P. species. ©

Dosage f v7
osage forms: aj]
\ Paz
* Tobramycin injection LP. 1
4. Gentamycin —
‘SMethy-4-(methylamino)
oxane-3 dol S-amine-6-1-(methyl
amino)ethy!

H.N~4 NH,

4,6-Dlamino-2-hydroxy
eyclohexyl]oxy)

61. Gentamycin C, CH, NHCH; H
Gentamycin Ca H NH, H
Gentamycin C, CH, NH; H
Gentamycin Cz, H NH, CH,

* Gentamycin is a mixture of C;, C?, and C,, compounds, obtained
commercially from Micromonospora purpurea.

* Gentamycin sulphate exists as white hygroscopic powder, soluble
in water, and practically insoluble in alcohol, although it is a

broad-spectrum antibiotic.
QUESTIONS FROM THE ABOVE TOPICS

(2 marks)

answer type que:

Very

estions (4 marks)

Short answer type ql

Long answer type questions (8 marks)

* Streptomycin is an aminoglycoside
antibacterial and antimycobacterial

© Itis biosynthesized by Streptomyces griseus.

62. * Streptomycin is an amino cyclitol glycoside that consists of Streptidine
having a disaccharyl moiety attached at the 4-position.

* It acts as a Triacidic base through the effect of its two strongly basic
guanidino groups and the more weakly basic methylamino group.

+ Structure

HN NH
ss Y
trihydroxy-cyclohexoxy)
Ho, NH on |
6
RN La Streptidine
we ww)
HC
EL CHO)” ony-s.nyarony-2-methyt
|, -tetrahydrofuran-3-carbaldehyde
3 L-Streptose
HO. HO 0

4-14,5-Dihydroxy-6-(hydroxymethyl
3-methylamino-tetrahydropyran-2-y1]

HO OH. NHCH, N-methyl-L-Glucosamine
+ Physical properties
* Streptomycin sulphate is a white hygroscopic powder, very soluble in
water, and practically insoluble in ethanol.

Streptomycin sulphate
+ Factors that limit the therapeutic use of Streptomycin are-
(1) Early development of resistant strains of bacteria. 7
(2) Neurotoxic reactions characterized by vertig« £ al a

disturbance of equilibrium and diminished
auditory perception.

63. (3) Ototoxicity, the possible development of damage to the optic nerve by
the continued use of streptomycin. ‘M

(4) Nephrotoxicity, need frequent
checks of renal monitoring
parameters. For systemic
action, streptomycin usually is
given by intramuscular
injection
Jses

* Streptomycin is active against numerous Gram-negative and Gram-

positive bacteria's.

* It is a broad spectrum aminoglycoside antibiotic used in treatment of
active tuberculosis, always in combination with other antituberculosis
agents.

* Itis used in eye

QUESTIONS FROM THE ABOVE TOPICS

fections

Very short answer type questions (2

Give the Structure of Streptomycin.

From which compound, Streptomycin is obtained ?
Short answer type questions (4 )
What are the factors that limit the use of streptomycin ?
Long answer type questions (8 marks)

Write a Note on streptomycin along with their uses.

NEOMYCIN }
Q INTRODUCTION

* Neomycin is isolated from Streptomyces fradiae.
* Neomycin is a broad spectrum aminoglycoside antibiotic and
shows a low incidence of toxic and hypersensitivity reactions.

64. ructure |

5-Amino-2-(aminomethyl) 3,5-dlamino-6-hydroxy |
tetrahydro-2H-pyran-3,4-diol cyclohexyloxy |

CH,NH, Ni, [Peowstreptamine

{ Neosamine C

HO

Neosamine B

7 3-amino-6-(aminomethyl)-
Ahydroxy-2-(hydroxymethyl) _ +S-dlhydroxytetrahydro-
tetrahydrofuran-3-yloxy) 2H-pyran-2-yloxy)

Neomycin is a mixture of three components

Neomycin Aisa Neomycin B (Framycetin). Epimer
disaccharide, also | Neomycin Bis composed of four | Neomycin
called Neamine, linked parts: D-neosamine, 2- c
contains D-neosamine | deoxystreptamine (2 - DOS) D-
and 2- ribose, and L-neosamine
deoxystreptamine
“= Uses

+ _ Neomycin considered one of the most useful antibiotics for the treatment

| ofgastrointestinal infections, dermatological infections, and acute
bacterial peritonitis.

+ Itis used in abdominal surgery to reduce infections from bacterial flora
of the bowel. Good bacterial fora @

©@@ “|

65. jort note on Ne

Q INTRODUCTION
* Kanamycin is an aminoglycoside bactericidal antibiotic isolated from the
bacterium Streptomyces kanamyceticus. —
Structure

* The mixture consists of three related structures, that
is, Kanamycin A, B, and C.

* The kanamycins do not possess D-ribose molecule
that is present in neomycins and paramomycins.

CHR,

Kanamycin A = Ry= NH; ; R= OH
Kanamycin B = R;=R;= NH,
Kanamycin C = R,=OH; R¿= NH

66. «+ Physical properties
* Kanamycin Sulfate is white, odourless crystalline powder.
* It has a potency equivalent to not less than 750 micrograms of kanamycin

per mg, calculated on the dried basis.
soluble in water; insoluble in acetone, in ethyl acetate, and in
benzene. pH of a 1% solution in water is between 6.5 and 8.5
* Store in airtight containers.

1Kanamycin is useful drug in the treatment of following conditions

Respiratory tract infections
Urinary tract infections

/ Blood, bone infections
Soft tissue infections

2. Kanamycin is useful drug in the treatment against following bacteria and
their infections $

Enterobacter aerogenes
Klebsiella pneumoniae

Serratia marcescens £

Acinetobacter species

QUESTIONS FROM THE ABOVE TOPICS

Short answer type questions (4 marks) |

Long answer type questions (8 marks)

67. Q INTRODUCTION

* They are potent, broad-spectrum antibacterial

agents effective against gram-positive and gram-
negative aerobic and anaerobic bacteria.

* They also play a role in the treatment of sexually
transmitted and gonococcal diseases, urinary tract infections,

4

bronchitis, and sinusitis remain prominent. em
+ Historical background
* In 1940s, a 71 years old Benjamin Minge Duggar head of
the soil engineering department identified tetracycline as a
therapeutic substance produced by soil microorganisms.
* At early stages, Tetracycline was first originated as a
fermentation product of golden colored soil bacterium
named Streptomyces aureofacians. Benjamin Minge
+ Mechanism of action Duggar
* The tetracyclines are primarily bacteriostatic.
* They inhibit protein synthesis by binding to 305 ribosomes in susceptible
organisms.
* Subsequent to such binding, attachment of aminoacyl-t-RNA to the
acceptor (A) site of mRNA-ribosome complex is blocked
* Asa result, the peptide chain fails to grow.
P ste ‘Aste

68. + Nomenclatures

* Tetracyclines have a ring system of four linear annelated six-membered
rings and are characterized by a common octahydronaphthacenes

skeleton.

4(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-
3,12-dloxo-4,4a,5,Sa-tetrahydrotetracene-2-carboxamide
+ Stereochemistry

© The stereochemistry of the tetracyclines is very complex.

* Carbon atoms 4, 4a,
on substitution.

* Oxytetracycline and doxycycline,
each with a Sa-hydroxyl
substituent, have six
asymmetric centers; the others,
lacking chirality at C-5, have
only five.

a, 6, and 12a are potentially chiral, depending

+ SAR of Tetracyclines

The key structural feature is a linearly fused tetracyclic nucleus and
each ring needs to be six membered and purely carbocyclic.

2. | Atetracyclic backbone skeleton is essential for acti

The D-ring needs to be aromatic and the A-ring must be
3. | appropriately substituted at each of its carbon atoms for notable
activity.

The B-ring and the C-ring tolerate certain substituent changes as long
4. | as the keto-enol systems (at C-11, 12, 12a) remain intact and
conjugated to the phenolic D-ring.

69. Modification of C-1
and C-3 position

The keto-enol tautomerism of ring A
carbon atom 1 and 3 is important , blocking
this system results in loss of antibacterial
activity

Modification of C-2
position:

The antibacterial activity resides on the
carboxamide moiety.

Modification of C-
4a position

The achydrogen at C-4a position of
tetracyclines is necessary for useful
antibacterial activity.

Modification of the
cs

Alkylation of the C-5 hydroxyl group results
in loss of activity.

Modification at the
C-6 position

The C-6 position is tolerant to a variety of
substituents.

C-7 substituents

Substitution with electron withdrawing
group such as nitro and halogen groups in
some C-7, produces the most potent of all
the tetracyclines

C-10 substituents

The C-10 phenolic moiety is necessary for
antibacterial activity.

70. + Classification of Tetracyclines
¥ According to Sources

Oxytetracyclines Methacycline
demeclocycline Doxycycline
Chlortetracycline Minocycline

tetracycline Meclocycline

Y” According to the duration of action

Intermediate acting
(Halflife 12 hrs) | on

Methacycline * $ \

Demeclocycline
\ LARA y

Short acting

Short acting
(Half life 6-8 hrs)
Tetracycline
Chlortetracycline

«+ Important products of Tetracyclines

id acting

Longacting |
(Halflife 16 hrs) |
Doxycycline

Minocycline |

1 Tetracyclines
2 Oxytetracycline
3 Chlortetracycline
4 Minocycline

5 Doxycline

71. NATURAL TETRACYCLINES

L Tetracycline a | cH, | 4
2. Chlortetracycline a | -m | +4
3. Oxytetracycline -H | -c | -oH
4. Bromotetracycline Br | cm | m ||

OH 0
i. Tetracycline
NH)
A (ci)
on
ur Tome

oH 0 on 0
4-(dimethylamino)-1,6,10,11,12a-
pentahydroxy 6-methyl-3,12-dioxo-
4,4a,5,Sa-tetrahydrotetracene-2-
carboxamide

H
0 120
ii. Chlortetracycline

cH, N(CH,
SoH ( n a

Ir None
oH 0 om 0
7-Chloro-4-(dimethylamino)-
1,6,10,11,12a-pentahydroxy-6-
methyl-3,12-dioxo-4,4a,5,5a-

tetrahydrotetracene-2-carboxamide

iii, Oxytetracycline

OH 0 OH 0

(4-(Dimethylamino)-3,5,6,10,11,12a-
hexahydroxy-6-methyl-1,12-dioxo-
1,4,4a,5,5a,6,12,12a-
octahydrotetracene-2-carboxamide

iv. Bromotetracycline

oH 0 OH 0

7-Bromo-4-(dimethylamino)-
1,6,10,11,12a-pentahydroxy-6-
methyl-3,12-dioxo-4,4a,5,5a-
tetrahydrotetracene-2-carboxamide

72. SEMISYNTHETIC TETRACYCLINES

DRU
1: Doxycycline -OH -H -CH, -H |
2. Minocycline Hi MH “| NCH)
3. Methacycline on - MH
4 Meclocycline -OH - “cl |
5. Sancycline Hi “H H |

4-(Dimethylamino)-3,5,10,12,12a-
pentahydroxy-6-
methylene-1,11-dioxo-
1,4,4a,5,5a,6,11,12a-octahydrotetracene-2- |
carboxamide |

iii, Minocycline

N(CH3)2 N(CH3)2
—> OH
«
‘cons; |
OH O0 OHNO

OH 0 04 120

| 4-(Dimethylamino)-3,5,10,12,12a- 2-(Amino-hydroxy-methylidene)-4,7- |

pentahydroxy-6-
methyl-1,11-dioxo-
5,5a,6,11,12a-octahydro
cene-2-carboxamide

14,
tet

bis(dimethylamino)-10,11,12a-

trihydroxy-
tetracene-1,3,12-trione[4]

73. Adverse effects

> Irritative effects
+ Tetracyclines have irritant property; can cause epigastric pair
nausea, vomiting and diarrhoea.

> Organ Toxicity
1. Liver damage
Fatty infiltration of liver and jaundice occurs, Tetracyclines are risky in
pregnant women; can precipitate fatal acute hepatic necrosis
2. Kidney damage er
Patients with kidney disease run theriskoftetracycline- Y uam

induced kidney damage. Tetracyclines, except

doxycycline, accumulate and worsen renal failure

3. Phototoxicity ( )
A sunburn-like or other severe skin reaction on

exposed parts is seen in some individuals. ARENA NOIRE

4. Teeth and bones
Tetracyclines have chelating property. Calcium-tetracycline
chelate gets deposited in developing teeth and bone

QUESTIONS FROM TE BOVE TOPICS
Very Short answer type questions (2 marks)

Short answer type questions (4 marks)

is m ae r )
L

Explain the SAI lines

74. Q INTRODUCTION

* Tetracycline is a broad-spectrum polyketide antibiotic produced by the
Streptomyces genus of actinobacteria.

* Tetracycline, sold under the brand name Sumycin among others, is
used to treat a number of infections. @

* Tetracycline was patented in 1953 and came into
commercial use in 1978. It is on the World Health
Organization's List of Essential Medicines. TETRAETEUmG

World Health
Organization
m

* Tetracycline is available as a generic medication.
*% Nomenclature

OH O HO HO o

4-Dimethylamino-1,4,4a,5,52.6.11.12a-octahydro 3,6,10,12,12a-
pentahydroxy-6-methyl-1,11-dioxo-naphthacene-2-carboxamide.

* In Tetracycline there are five chiral centres, and each of these centres has
S configuration.
* Itisa yellow, erystalline powder It darkens in strong sunlight in a moist
atmosphere.
* Itis very slightly soluble in water.
+ Dose:
250-500 mg QID or TDS

Uses

* It is used in infections by certain intracellular bacterial pathogens such
as Chlamydia, Mycoplasma, and Rickettsia

* Since tetracycline is absorbed into bone, it is used as a marker of bone
growth for biopsies in humans.

75. + The tetracyclines also have activity against certain eukaryotic parasites,
including those responsible for diseases such as dysentery caused by
an amoeba, malaria (a plasmodium), and balantidiasis

QUESTIONS FROM THE ABOVE TOPICS

1. Write the structure of Tetracycline

2. Give the IUPAC name for Tetracycline.

Q INTRODUCTION
* Oxytetracycline is a tetracycline used for treatment of infections caused by
a variety of Gram positive and Gram negative microorganisms
* It has a role as an antibacterial drug, a protein synthesis inhibitor, an
antimicrobial agent, an anti-inflammatory drug and a bacterial metabolite.
Itis a tautomer of an oxytetracycline zwitterion.
* It was first found near Pfizer laboratories in a soil sample yielding the
soil actinomycete, Streptomyces rimosus
+ Nomenclature

H3C OH OH UN.
H3C~ CH;
Oxytetracycline

4-(Dimethylamino)-3,5,6,10,11,12a-hexahydroxy-6-methyl-1,12-dioxo-
1,4,4a,5,5a,6,12,12a-octahydrotetracene-2-carboxamide

76. + Physical properties
* Oxytetracycline is pale yellow to tan, odourless crystalline
powder, that darkens on exposure to strong sunlight.
+ sparingly soluble in alcohol; practically insoluble in chloroform;
freely soluble in 3N hydrochloric acid and in alkaline solutions.
* pH of a 1% suspension in water is between 4.5 and 7.0.
* It loses potency in solutions of pH below 2 and is rapidly
destroyed by alkali hydroxide solution.
* Itshould be protected from light.
+ Dose:

* PO- The recommended dose range is 250 to 1.5gm in divided doses.

+ Topical- Apply a thin layer over the affected skin 4 times per day.

Uses
Oxytetracycline is an alternative drug in the treatment of leptospirosis,
gas-gangrene and tetanus
The tablets are for oral administration and are best taken on an empty

stomach. If gastric irritation occurs, tablets should be taken with food.
Occasionally, oxytetracycline is given by intramuscular injection or
topically in the form of creams, ophthalmic ointments or eye drops.
Oxytetracycline is used to treat infections of the respiratory and urinary
tracts, skin, ear, eye and gonorrhea

QUESTIONS FROM THE ABOVE TOPICS

-y Short ansv
1. Write the structure of Oxytetracycline
2. Give the IUPAC name for Oxytetracycline.

and usual dose of Oxytetracycline

77. Q INTRODUCTION
* Chlortetracycline is a member of the class of
tetracyclines isolated from Streptomyces aureofaciens.

+ It has a role as an antiprotozoal drug, a fluorescent £
probe, a calcium ionophore and an antibacterial drug.

Pe Streptomyces

History aureofaciens.

* Chlortetracycline is the first member of tetracycline class to be identified.

* It was discovered in 1945 by the scientist, Benjamin Minge Duggar, working
at Lederle Laboratories under the supervision of Yellapragada Subbarow. |

* He discovered that this antibiotic was the product of an actinomycete strain
he cultured and obtained from a soil sample from a field in Missouri.

+ Nomenclature

7-Chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-
methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-

carboxamide
Dose: de

* Usual daily dose: 500 mg in 12hr or 250 mg in 6hr * po
+ Uses

* A combination cream with triamcinolone acetonide is Zn

available for the treatment of infected allergic
dermatitis in humans.

* In veterinary medicine, chlortetracycline is commonly
used to treat conjunctivitis in cats, dogs and horses.

78. * Itis also used to treat infected wounds in cattle, sheep and pigs,
and respiratory tract infections in calves, pigs and chickens.
* Itis marketed in ointment forms for topical and ophthalmic use.

QUESTIONS FROM THE ABOVE TOPICS

1. Write the structure of Chlortetracycline.
e the IUPAC name for Chlortetracycline.
vel io!

1. Write uses and usual dose of chlortetracycline.

MI

CYCLINE
Q INTRODUCTION

* Minocycline, is a tetracycline antibiotic medication used to treat a number
of bacterial infections such as pneumonia
* Itis generally less preferred than the tetracycline doxycycline.

* Itis also used for the treatment of acne and rheum:

* Itis taken by mouth „IV ‚and applied to the skin]
History

* Minocycline was patented in 1961 and came into commercial use in 1971.

* A topical foam for treatment of acne was approved in 2019,

Nomenclature
* Minocycline is a tetracycline analogue having a dimethylamino group at
position 7 and lacking the methyl and hydroxy groups at position 5.

N(CH3)2

2-(Amino-hydroxy-methylidene)-
4,7-bis(dimethylamino)-10,11,12a-
trihydroxy- tetracene-1,3,12-
CONH, trione[4]

OH
0 OHO

79. Physical properties
* Minocycline is yellow crystalline powder. Sparingly
soluble in water ; Slightly soluble in alcohol; practically
insoluble in chloroform.
* Minocycline should be in airtight containers.
* Itshould be protected from light.
+ Dose:
The dose orally for adults is 200 mg
+ Uses
* Itis very active against gram-positive bacteria,
* Itis especially effective against Mycobacterium marinum.
* Asa prophylactic against streptococcal infections, it is
the drug of choice.
* Itlacks the 6-hydroxyl group, therefore, it is stable to
acids and does not dehydrate or rearrange to anhydro
or lactone forms.

QUESTIONS FROM THE ABOVE TOPICS

Very Short answer type question:

1. Write the structure of Minocycline

2. Give the IUPAC name for Minocycline and its Dose.
Long answer type questions (8 marks]
1. Describe Minocycline.

OXYCYCLIN
Q INTRODUCTION

* Doxycycline is a broad-spectrum tetracycline-class antibiotic used in the
treatment of infections caused by bacteria and certain parasites.

* Itis used to treat bacteria pneumonia, acne, Lyme disease, and syphilis.

* Itis also used to prevent malaria in combination with quinine.

* Doxycycline may be taken by mouth or by injection into a vein.

80. + Historical background
* After the invention of tetracycline, Charlie
Stephens’ group at Pfizer worked on further
analogs and created one with greatly improved
stability and pharmacological — efficacy:
doxycycline.

+ It was clinically developed in the early 1960s Doxycycline was
patented in 1957 and came into commercial use and approved
by the FDA in 1967.

“ Mechanism of Action
* Doxycycline reversibly bind to the 30S subunit at the A-site to prevent
attachment of the amino acyl tRNA, terminating the translation process

Nascent

polypeptide u

chan

à —Transterase

ste
Dowyeycine
mana
template

+ Nomenclatures

4-(Dimethylamino)-3,5,10,12,12a-pentahydroxy-6-
methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro
tetracene-2-carboxamide

81. + Physical properties
* A yellow crystalline powder. Very slightly soluble in
water sparingly soluble in alcohol
* Storage should be in airtight container and protected
from light.
© It was first obtained in small yields by a chemical transformation of
oxytetracycline.
* The 6a-methyl epimer is more than three times as active as its B epimer.
+ Dose:
* Inadults, the oral dosage is 100 mg every 12 h.
+ Dosage forms:
* Doxcycline HCl capsules LP, Doxcycline HCI tablets 1.P.

+ Uses
1. It is used in the treatment of infections caused by Gram +ve & -ve
bacteria, like the respiratory tract, eye infections, UTIs
2. Doxycycline has recently been used in prevention of cancer recurrence.
3. Doxycycline used in the treatment of infections like syphilis sinusitis,

oral herpes simplex, acne and malaria. > e & Sn
4. Itis also used in amoebiasis. > F e wi?
+

a

ery Short answe
What are the physical p
What is the dose of dox;

What are the uses of doxycy

Give the IUPAC name for doxycyc

Explain Doxycycline along with its structure