penicillin IS Antibiotics

1. MEDICINAL CHEMISTRY 3.215
Sr. no Name of drug R1
R3
R4
Rc3
Rc4
1 Meperidine CH3
H COOC2
H5
H H
2 Bemindone CH3
H COOC2
H5
OH H
3 Trimeperidine CH3
CH3
OCOC2
H5
H H
CHEMOTHERAPY
Antibiotics
E-Lactam Antibiotics-Penicillin and
Cephalosporin Penicillin
It is obtained from Penicilin Notatum and Penicillin Chrys-
ogenam.
S
Me
Me
OH
Ring B
Ring A
N
NH
O
O
R
O
y Ring A is a four membered E-Lactam ring (cyclic am-
ide)
y Ring B is a five membered Thiazolidine ring
y Degradation product of penicillin:
s At acidic pH-Penillic Acid
s At basic pH-Penicilloic acid
y Certain strands of micro organism destroy
E-Lactam antibiotics enzymatically like Penicilla-
nase or E-Lactamase (Open the E-Lactam ring).
Stereochemistry and IUPAC of -Lactam ring
S
N
Me
Me
NH
OH
O
O
H H
R
O
y It has total three chiral carbon like 3, 5 and 6.
y All synthetic and semi synthetic penicillin having same
absolute configuration (like 3S and 5R, 6R).
y Acyl amino and carboxylic acid Trans to each other.
y The lead molecule in the discovery of semi synthetic
penicillin is 6 amino penicillinic acid (6-APA).
y 6-APA structurally derived from L-Valine and L-cysteine
y All penicillins has Penam ring as a basic moiety.
S
N
1-Aza-4-thia-Bicyclo [3.2.0] heptane
Penam Ring
Classification
1. Fermentation derived penicillin
S
N
Me
Me
NH
OH
O
O
R
O
6-APA
Benzyl Penicillin
Phenoxy methyl
penicillin (Pen-V)
R
H
(Pen-G)
CH2
O
2. Semi synthetic penicillanase resistance
penicillin: Parenteral Penicillin
E.g., Methicillin, Nafcillin
S
N
Me
Me
NH
OH
O
O
R
O
R
CH3
O
CH3
O
C2H5O
Methicillin
Nafcillin
Methicillin-2, 6-Dimethoxy phenyl penicillin
Nafcillin-2-Ethoxy-1-Napthyl-Penicillin
Thiazolidine ring
E
E-
-
-
-Lactam ring (cyclic am-
ide)
Ring A
Ring B
Ring A
Ring B
At acidic pH-Penillic Acid
At basic pH-Penicilloic acid
destroy
E
E-
-
-
-Lactam antibiotics enzymatically like Penicilla-
E
E-
- E-
nase or -Lactamase (Open the
- -Lactam ring).
three chiral carbon
r
r like 3, 5 and 6.
(like 3S and 5R, 6R)
6 amino penicillinic acid (6-APA).
6-APA structurally derived from L-Valine and L-cysteine
penicillins has Penam ring as a basic moiety.
Penam Ring
(Pen-G)
(Pen-V)
Benzyl Penicillin
Phenoxy
x
x methyl
penicillin
R
H
Semi synthetic penicillanase resistance
penicillin: Parenteral Penicillin
E.g., Methicillin, Nafcillin
Methicillin
Nafcillin
-2-Ethoxy-1-Napthyl-
-2, 6-Dimethoxy phenyl p
Methicillin-
-
Nafcillin-
-

2. 3.216 CHAPTER 5
3. Semi synthetic penicillanase resistance penicillin: Oral Penicillin
y It contains isoxazole as a basic moiety.
y 5-Hydroxy methyl penicillin derivative is a metabolite.
y It is applicable to penicillin sensitive patients.
S
N
Me
Me
NH
OH
O
O
R
O
R
O
N
CH3
O
N
Cl
O
N
Cl
Cl
Oxacillin
Cloxacillin
Dicloxacillin
CH3
CH3
y Oxacillin-5-Methyl-3-Phenyl-4-isoxazolyl penicillin
y Cloxacillin-5-Methyl-3-(2-chlorophenyl)-4-isoxazolyl penicillin
y Dicloxacillin-5-Methyl-3-(2, 6-di chlorophenyl)-4-isoxazolyl penicillin
Extra halogen is responsible for increasing fraction bound to protein in the plasma potentially reduce the concentration
of free antibiotics in plasma and tissue.
NOTE
4. Semi synthetic penicillanase sensitive
broad spectrum parental penicillin
(Anti psedomonal penicillin-Ticarcillin, Carbencillin)
S
N
Me
Me
NH
OH
O
O
R
O
R
COOH
Carbencillin
S
COOH
Ticarcillin
Ticarcillin is an isoster of carbencillin, and it having
thiophene ring azlocillin.
S
N
Me
Me
NH
OH
O
O
R
O
R
CH-
NH
CO
N
N
O
SO2CH3
Mezlocillin
Azlocilin: SO2
CH3
is replaced by H.
isoxazole
Semi synthetic penicillanase resistance penicillin: Oral Penicillin
Oxacillin
Cloxacillin
Dicloxacillin
R
-5-Methyl-3-Phenyl-4-isoxazolyl p
h
h
-5-Methyl-3-(2-chlorophenyl)-4-isoxazolyl p
-5-Methyl-3-(2, 6-di chlorophenyl)-4-isoxazolyl p
Semi synthetic penicillanase sensitive
broad spectrum parental penicillin
(Anti psedomonal penicillin-Ticarcillin, Carbencillin)
R
Carbencillin
Ticarcillin
isoster
azlocillin.
thiophene ring
g
Mezlocillin
Azlocilin:

3. MEDICINAL CHEMISTRY 3.217
Azlocillin and mezlocillin have Oxoimidazolidino
basic moiety.
Piperacillin: has dioxo piperizine
S
N
Me
Me
NH
OH
O
O
R
O
R
CH-
NH
CO
N
N
O
O
SO2CH3
Piperacillin
SAR of penicillin
y All E-lactam antibiotics contain 4 membered E-lactam
rings fused with N atom and tetrahedral carbon to a
second heterocyclic ring.
Penicillin
(Penam Ring)
Thiazolidine
S
NH
2
3
4
5
1
Thienamycin
(Carbapenam)
E-lactam
N
O
Pyrrolidine
N
Clavulanic acid
(Oxapenam)
Oxazolidine
O
N
Cephalosporin
(Cepham Ring)
Dihydrothiazine
N
S
R
COOH
y Penicillin is unstable under acidic and basic condition so
manipulation of polar amide groups leads to increased
potency as well as chemical and physical stability.
y Introduction of chemical inducer/precursor in culture
medium leads to increasing quantity as well as quality
of penicillin production.
E.g., phenyl acetic acid is added as a chemical inducer
in production of 6-APA.
y Some bacteria like gram negative bacilli are resistant
to action of penicillin due to production of E-lactamase
enzyme. So many semi synthetic penicillin were devel-
oped by manipulation of C-6 polar amide group.
y Increasing steric hindrance at D carbon of acyl group
increases resistance to staphylococcal E-lactamase like
substitution of Aromatic (Phenyl, Napthyl) ring or any
heterocyclic ring (Isoxazoyl-Oxacillin, Cloxacilln) or
ring substitution at ortho position (2, 6 dimethoxy
substitution on phenyl ring of methicillin) and (2 ethoxy
substitution on napthayl ring of Nafcillin).
y Incorporation of an ionized/polar/acidic substitution on
D carbon of side chain of benzyl carbon atom of benzyl
penicillin increasing activity against gram negative bacilli.
E.g., Ampicillin, Amoxicillin, Carbencillin
y All natural penicillins are dextrorotatory.
Depot preparation of penicillin-having limited water
solubility and release drug over a longer periods.
E.g., Procaine Penicillin-Amine salt of penicil-
lin G with procaine
Benzathin Penicillin
Hydrabamine penicillin
Mechanism of E-lactam antibiotics
y Inhibition of bacterial cell wall synthesis by inhibiting
the synthesis/production of peptidoglycan.
y Cell wall of bacteria is essential for normal growth and
development.
y Peptidoglycan is an essential constitutent of bacterial
cell wall, and it is a heteropolymeric components of
cell wall responsible for the providing stability.
y Glycan chain is made up of two alternating amino
sugar (NAM-N-Acetyl muramic acid) and (NAG-N-
Acetyl Glucosamine) by peptide linkage.
E lactam rings Name of ring Examples
Penam Penicillin
Oxoimidazolidino
Azlocillin and mezlocillin
Piperacillin
N
N
dioxo piperizine
O
O
E-
4 membered -lactam
rings fused with N atom tetrahedral carbon to a
second heterocyclic ring.
(Penam Ring)
(Carbapenam)
(Oxapenam)
(Cepham Ring)
Thiazolidine
Pyrrolidine
Oxazolidine
E-
-lactam
Dihydrothiazine
of polar amide groups
r
r leads to increased
potency as well as chemical and physical stability.
f chemical inducer/precursor in culture
r
medium leads to increasing quantity as well as quality
of penicillin production.
phenyl acetic acid
f 6-APA.
f C-6 polar amide group.
D
steric hindrance at carbon of acyl group
E-
increases resistance to staphylococcal -lactamase
(Phenyl, Napthyl)
(Isoxazoyl-Oxacillin, Cloxacilln)
(2, 6 dimethoxy
substitution on phenyl ring of methicillin) (2 ethoxy
substitution on napthayl ring of Nafcillin)
ionized/polar/acidic substitution on
D carbon of side chain of benzyl carbon atom of benzyl
penicillin increasing activity against gram negative bacilli.
All natural penicillins are dextrorotatory.
Depot preparation of penicillin-having limited water
solubility and release drug over a longer periods.
Procaine Penicillin-A
Benzathin P
Hydrabamine p
inhibiting
the synthesis/production of
r
r peptidoglycan
f
f .
Glycan chain
(NAM-N-Acetyl muramic acid) (NAG-N-
Acetyl Glucosamine) peptide linkage.
Penam Penicillin

4. 3.218 CHAPTER 5
E lactam rings Name of ring Examples
Cepham
Cephem
Cephalosporins
.....................
Carbapenam
Carbapenem
Thienamycin,
Imipenam,
Meropenam
Biapenam
(E lactamase
inhibitors)
Oxapenam Clavunic acid
(E lactamase
inhibitors)
Penam-1,
1-Dioxide
Salbactum,
Tazobactam
Monobactam Saulfazecin,
Aztreonam,
Tigemonam
(E lactamase
resistance agent)
CEPHALOSPORIN
Source: Cephalosporium Acremonium
R2
O N
S
O
NH
R1
COOH
Ring A
Ring B
Cepham ring IUPAC-5-Thia-1-Aza-Bicyclo[4.2.0] Oct-
2-ene
y Ring A is a four membered E-Lactam ring (cyclic
amide)
y Ring B is a six membered Dihydrothizine ring.
y Cephalosporin having cepham as a basic moiety
y Like 6-APA in penicillin, 7-Amino cephalosporic
acid is a lead molecule for synthesis semi synthetic
cephalosporin
y Cephalosporin C-True cephalosporin or 7-ACA
y Cephalosporin P-Acidic antibiotics or Steroidal
antibiotic (Fusidin)
y Fusidin-It is sodium salt of fusidic acid.
y Cephalosporin N-Derivative of 6-APA, Also
known as Synnnematin N now a days, it is known as
Penicillin N.
y Semi synthetic cephalosporin prepared by modifica-
tion in
y Acylation of 7-Amino cephalosporic acid.
y Reduction of 3-Acetyloxy group.
O
O
H
NH2
O N
S
O
NH
COOH
O
H H
CH2
O
Alfa amino adipoyl side chain
Cephalosporic Acid (Cephalosporin C)
(If α Amino adipoyl side chain is removed from
Cephalosporin C by breaking of amide bond to structure
of 7ACA)
MACROLIDE ANTIBIOTICS
Sources: Actinomycetes
Common Structural features of Macrolide antibiotics
y A many membered (12, 14 and16 atoms) lactone ring-
hence named Macrolide
y Various ketonic and –OH functional group.
y Glycosidically linked to 6-deoxy sugar
Picromycin first identified drug of Macrolide
antibiotics.
y E.g., Spiramycin, Oleanlomycin, Erythromycin
y Semi-synthetic derivative of erythromycin
Cepham
Carbapenam
Carbapenem
Oxapenam
Penam-1,
1-Dioxide
Monobactam
Ring A
Ring B
E
E-
-Lactam ring (cyclic
amide)
Dihydrothizine ring.
h
h
cepham
6-APA in penicillin,
P
P 7-Amino cephalosporic
acid i semi synthetic
cephalosporin
Cephalosporin C-T
Cephalosporin P-A
Fusidin-
Cephalosporin N-Derivative of 6-APA,
Penicillin N.
CH
H2
Acylation of 7-Amino cephalosporic acid.
Reduction of 3-Acetyloxy group.
Alfa amino adipoyl side chain
α
(If Amino adipoyl side chain is removed from
Cephalosporin C by breaking of amide bond to structure
of 7ACA)