Download Uses

Lecture 5
Medicinal Chemistry 1
PC 509
Prof. Dr/ Ghaneya Sayed Hassan
[email protected]
1
Macrolides
Properties:
• Isolated form Sterptomyces species.
• Lead compound is Erythromycin.
Spectrum:
• Nearly as penicillin G  narrow spectrum [used as alternative
for patients allergic to penicillins].
• Drug of choice for chlamydial infections, mycoplasma,
pneumonia, Corynebacterium diphtheriae & Ligionella
pneumophila.
M.O.A: Specific inhibitor of bacterial protein
biosynthesis by binding to the 50S ribosomal subunit
 interfere with translocation reactions & formation of initiation
complexes  inhibit protein synthesis  bacteriostatic [may be cidal
at  doses]
Safe to human [not affect 60 S unit]  selective chemotherapy.
2
Resistance: due to:
1) Inability of m.o. to take up the drug.
2) Produce enzymes that methylate specific adenine residue to
erythromycin binding site   affinity of erythromycin to bind.
3) Presence of plasmid-associated erythromycin esterase.
Side effects:
(1) GIT problems.
(2) Cholestatic jaundice: especially with Erythromycin Estolate [result
from hypersensitivity reaction  bile becomes granular in bile duct 
 its flow  back up into circulation].
(3) Ototoxicity: transient deafness [especially at  doses].
(4) Erythromycin  level of simultaneously administered anticoagulants, anti-diabetetics, cyclosporine, carbamazepine…. By
inhibition of microsomal enzymes.
“Metabolizing microsomal enzymes’ inhibitors”
(5) Not used for patients with hepatic dysfunction  drug
accumulation in liver.
3
Chemical properties:
(1) Large lactone ring [cyclic ester] with 12-17 atoms  so, the
name Macrolides.
(2) With 2 or more sugars attached to this ring  one of them is
amino sugar [so, marcrolides are weakly basic].
(3) Free bases are water insoluble.
Stability:
In neutral medium  macrolides are stable.
In acidic medium  hydrolysis of glycosidic bonds.
In basic medium  saponification of lactone ring
[opening].
4
Erythromycin
 Obtained by fermentation of Sterptomyces erythereus.
Desosamine
CH3
O
CH3
HO
11
12
CH3
C2H5
8
9
10
HO
7
CH3
6
HO
R1
O
Erythronolide
2
O
CH3
6'
CH3
1' O 5'
2'
CH3
3'
CH3
OH
Oxo
Ethyl
6''
O 5'' CH3
CH3
3
14
O 1
O
1''
5
4
13
2''
2,4,6,8,10,12
3,5,6,11,12
1,9
13
N - Me2
3''
4''
4'
R1
R2
Erythromycin A
OH
CH3
Erythromycin B
H
CH3
Erythromycin C
OH
H
OH
OR2
 Used usually
as mixture of
90%
Erythromycin A
+
10%
Erythromycin B
+
traces of
Erythromycin C.
Cladinose
Consist of :
► Erythronolide [aglycone part, large lactone ring, 14-membered ].
► Desosamine [amino sugar]
►5 Cladinose [neutral sugar].
To overcome its bitter taste & its irregular absorption:
Result from acid destruction & adsorption of food.
(1) Enteric coated & delayed-release dose dosage forms:
Over come bitter taste but not solve problem of poor absorption.
(2) Erythromycin Salts:
Salts formed on dimethyl amino group of Desosamine.
☻HCl salt  moderate solubility.
☻ Glucepate & Lactopionate  freely soluble in water  I.V.
☻ Stearate  with  solubility  tasteless [combined with enteric
coating]  hydrolyzed in intestine to free erythromycin  absorption.
(3) Erythromycin Esters:
Estolate: [C2’’-propionyl ester] & [N-lauryl sulfate salt]  with superior
oral absorption [ acid stable +  intrinsic absorption + oral
absorption not affected by food].
Ethyl succinate: mixed double ester [ one carboxylic of succinic acid
react with C2’’ of erythromycin & other carboxylic react with ethanol].
It’s insoluble in water [used as oral suspension for pediatrics as it
masks bad taste of erythromycin]
6
SALT
ESTER
Desosamine
CH3
O
CH3
HO
RO
9
10
CH3
HO
6
O
CH3
O
OH
CH3
C2H5
R
Salt
1. Erythromycin Base
H
-----
2. Erythromicine HCl
H
HCl
COCH2CH3
CH3(CH2)11OSO3H
N - Me2
3. Erythromicine Estolate
4. Erythromycin Ethylsuccinate
CH3
O
14
O
O
CH3
CH3
O
Erythronolide
CH3
OH
OCH3
CO(CH2)COOC2H5
-----
5. Erythromycin Gluceptate
H
Glucoheptanoic acid
6. Erythromycin Lactobionate
H
Lactobiono-S-lactone
7. Erythromycin Stearate
H
CH3(CH2)16COOH
Cladinose
N.B: Erythromycin esters not considered as latent prodrugs, as they
are active itself & their activity not depend on their hydrolysis. But they are
partially hydrolyzed to free drugs in blood.
7
Erythromycin is Unstable to Acids due to Rapid Cyclic Ketal formation
 inactivation + GIT cramps.
H+
H+
N - (CH3)2
O
HO
OH
12
HO
O
O
HO
O
O
- H2 O
OH
O
O
O
O
O
O
OH
OCH3
Active Macrolide
RO
RO
HO
O
6
N - (CH3)2
N - (CH3)2
RO
9
O
Hemiketal
O
HO
O
O
O
OH
OCH3
O
O
O
O
O
Cyclic Ketal
OH
OCH3
Inactive + causing GIT cramps
So, we make semi-synthetic analogues to
prevent this ketal formation.
8
Semi-synthetic analogues
Clarithromycin [Klacid®]
CH3
N - Me2
HO
O
CH3
CH3
HO
CH3O 6
O
CH3
O
OH
CH3
C2H5
CH3
O
O
O
CH3
CH3
O
CH3
OH
OCH3
 Semi-synthetic drug from erythromycin by methylation of 6-OH 
etherification.
 6-OH involved in ketal formation which form inactive drug + GIT cramps.
 Methylation of 6-OH  ADVANTAGES:
(1) No cyclic ketal formation [inactivation + GIT cramps].
(2)  absorption & better blood level.
(3)9  lipophilicity   & less frequent dose for mild infections.
(4)  gastric upset.
Azithromycin [Zithromax®, Azithrocin®]
CH3
9
CH3
8
N - Me2
HO
N 9a
CH3
HO
10
CH3
HO
O
CH3
O
OH
CH3
C2H5
CH3
O
O
O
CH3
CH3
O
CH3
OH
OCH3
 Semi-synthetic  ring-expanded analogue [15-membered] by
insertion of N-methyl between C9-C10 + removal of C=O.
 Not form internal cyclic ketal.
 ADVANTAGES :
(1) No cyclic ketal formation [inactivation + GIT cramps]
(2) More acid stable.
(3) With longer duration [once daily]
10 Greater G-ve activity > Erytho- & Clarithromycin.
(4)
Chloramphenicol
O
H
O2N
1
NH
2
Cl
C CH
Cl
3
CH2 OH
OH H
D(-) threo-2,2-dicloro acetamido-1-(4-nitro phenyl) propane-1,3-diol
►Natural antibiotic; produced by fermentation of Streptomcyes
venezuelae. But now produced by total synthesis [less expensive].
►Used orally or I.V.
11
Spectrum:
1) Broad spectrum, active ≠ rickettsial infections.
2) Drug of choice in Salmonella infections [typhoid fever].
3) against H.influenza, -lactamase producing strains &
meningococcal infections.
4) With excellent activity ≠ anaerobes.
5) Now mostly used as eye drops for ophthalmic infections.
M.O.A:
Binds to 50 S ribosomal subunits 
interfere with action of peptidyl transferase
block attachment of amino acids
to nascent peptide chain on ribosomes 
inhibit protein synthesis  Bacteriostatic.
12
Side effects:
(1) Bone marrow depression:
May cause fatal blood dyscrasias [aplastic anemia, hypoplastic
anemia, thrombocytopenia & granulocytopenia].
(2) Gray syndrome: form of CVS collapse;
Occur when given for premature & newborn infants [with undeveloped
glucuronidation & undeveloped renal function]  accumulation of
chloramphenicol  poor feeding,  breathing, CVS collapse [gray
baby] & death.
So, not recommended in 1st two weeks of life.
(3) Inhibition of hepatic mixed function oxidases:
block metabolism of drugs e.g. warfarin,
tolbutamide , phenytoin
  their concentration.
13
Metabolism:
• Mainly excreted in urine.
• Major metabolite is C7-glucuronide, Minor obtained by
deamination, dehalogenation & reduction of aromatic nitro group [all
metabolites are inactive].
Resistance:
Occur due to:
(1)  dose.
(2) Irregular use.
(3) Inappropriate use.
(4) Production of enzymes  chloramphenicol acetyl transferase 
acetylation of 1-OH & 3-OH  1-acetoxy & 1,3-diacetoxy
derivatives  inactive.
(5) Inability of the drug to penetrate m.o.
14
SAR:
Replacement of phenyl group with:
- aromatic or alicyclic moities --> inactive Cpds
- Nitrothienyl derivative has activity <<
chloramphenicol.
(*) two chiral centres is essential for activity
& only D- (-) (1R,2R) threo has marked activity.
H
O 2N
*
C
OH
- NO2 if replaced with strong
electronwithdrawing gps ----> active cpds
e.g. Acetyl gp ( cetophenicol )
& Methyl sulphonyl ( thiamphenicol)
- if replaced by CN , CONH2 , halogen , OH &
SO2R----> inactive cpds
- NO2 shifting from P-position ----> reduce
activiry.
15
*
NH
R
C
CH2
OH
H
The amine propanediol side chain is the most specific
part:
- 1ry alcohol & 2ry alcohol ----> essential for activity
- Me subistitution for H on C2 -----> No activity.
- If R= CH2N3 (azidamphenicol ) OR R= COCHBr2
-----> Both give active Cpds.
N.B. The following are active compounds:
Cetophenicaol
Thiamphenicol
O
O
O
H3C
C
NH
1
OH
2
C
CH2
3
O
CH(Cl)2
H3C
OH
S
1
OH
O
NH
2
Azidamphenicol
O2N
1
OH
NH
2
CH2
CH2
3
N3
O2N
OH
1
OH
O2N
1
16
CH2
3
CH(Cl)2
OH
O
O
S
C
OH
NH
2
C
CH2
3
CH(Cl)2
OH
Less active than chloramphenicol
NH
2
C
CH2
3
CH(Br)2
OH
Prodrugs of chloramphenicol: [C3-esters]
Chloramphenicol Chloramphenicol
Palmitate
Hemisuccinate
O
H NH
O2N
1
2
O
Cl
H NH
C CH
Cl
3
CH2 O CO
(CH2)14 CH3
OH H
Insoluble in water.
To overcome bitter taste.
Used for pediatric oral
suspensions.
O2N
1
2
Cl
C CH
Cl
3
CH2 O CO
CH2 CH2 COOH
OH H
Water soluble  used for
injection to overcome poor water
solubility.
Esters are inactive  hydrolyzed in vivo releasing active form.
17
Stability:
• Very stable in solid form.
• In solution  hydrolytic & light-induced reactions; depending on pH,
heat & light:
[1] Acid-catalyzed hydrolysis of amide:
O
H
1
O2N
NH
2
Cl
C CH
H
Cl
3
CH2 OH
O2N
OH H
1
NH2
2
3
CH2 OH
+
O
HO
Cl
C CH
Cl
OH H
1-(p-nitrophenyl)-2-amino propan-1,3-diol
dichloro acetic acid
[2] Alkaline hydrolysis of -chloro  ,-dihydroxy derivative.
O
H
O2N
1
NH
2
OH H
18
Cl
O
C CH
Cl
3
CH2 OH
H
O2N
1
NH
2
OH H
OH
C CH
OH
3
CH2 OH
Synthesis of Chloramphenicol:
O
O2N
C CH3
Br2
Ac-OH
1. Hexamine
(CH2)6N4
O
O2N
C CH2 Br
O
O2N
2. HCl
P-nitro acetophenone
O
OH
NH C CH3 Al isopropoxide
O2N
C CH
O2N
H
CH2 OH
no reduction for NO2
Erythro + Threo
O
O2N
DL-threo
19
Resolution
D-(+) camphor
sulfonate
CH2O
NH C CH3
C CH
CH2 OH
fractional crystallization
H+
NH2
C CH
H
CH2 OH
C CH2 NH2
Acetic anhydride
O
OH
.HCL
NaHCO3
O
OH
O2N
NH2
C CH
H
CH2 OH
D(-)-threo
Cl
C
O
O2N
C CH2 NH C CH3
Cl
CH
Cl
dichloroacetyl Cl
O
Cholramphenicol
Mechanism of action:
1- -lactam antibiotics: Inhibitors of cell wall synthesis.
2- Tetracyclines: Bind to 30 ribosomal subunit of bacteria
interfere with protein biosynthesis leading
to bacteriostatic.
3- Aminoglycosides: Bind to 30 S ribosomal subunit of
m.o. through specific receptor protein  inhibit initiation
of protein synthesis.
4- Macrolides: Bind to 50 S ribosomal subunit 
inhibit protein synthesis.
5- Chloramphenicol: Bind to 50 S ribosomal subunits
inhibit protein synthesis.
20
Cyclic peptides antibiotics
The usual physiologically significant peptides are linear.
Several bacterial species, however, produces antibiotic
mixtures of cyclic peptides some with uncommon amino
acids and some with common amino acids but with the D
absolute stereochemistry. These cyclic substances often
have a pendant fatty acid chain.
Mode of action:
(Disruption of bacterial membrane function)
These drugs are usually water soluble and are highly lethal
to susceptible bacteria as they attach themselves to the
bacterial membrane and interfere with their semi
permeability so that essential metabolites leak out and
undesirable substances pass in.
21
Side effects:
They are highly toxic in humans so their use is reserved for serious
situations where there are few alternatives or to topical uses.
Resistance:
Bacteria are rarely able to develop significant resistance to this group of
antibiotics.
Stability:
They are generally unstable to solutions should be protected from heat,
light and extremes of pH.
Cyclic peptides antibiotics:
They are:
1-Vancomycin
2- Teicoplanin
3-Quinupristin
4-Dalfopristin (=Streptogramins).
5-Capromycin
6-Bacitracin
7-Polmyxin B
8-Colistin
22
Bacitracin
It is a mixture of similar peptides produced by fermentation of Bacillus subtilis.
Uses:
It is active mainly against gram (+) microorganisms and is used topically or
intramuscularly against staphylococci resistant to other agents. It is also
used orally for enter pathogenic diarrhea and, especially, against
Clostridium difficile. It can also be used for preoperative bowel sanitization.
It is neuro and nephrotoxic restricted in uses. Zn2+ enhances its activity.
Mode of action:
1- Inhibition of peptidoglycan
biosynthesis.
2- Disruption of plasma
membrane function.
23
Polymyxin B
It is produced by fermentation of Bacillus polymyxa.
Uses:
It is active against gram (-) microorganisms. It is used I.M or I.V to treat
serious urinary tract infections, meningitis and septicemia caused by
Pseudomonas aeruginosa. It is also used orally to treat enter pathogenic
E. coli and Shigella sp. diarrheas. It is neuro and nephrotoxic especially
when given parentrally (restricted in uses).
Mode of action:
It binds to phosphate groups in
bacterial cytoplasmic membranes
and disrupts their integrity.
24
Colistin
Colistin sulphate is a cyclic polypeptide drug produced by Bacillus
polymyxa var. colistinus.
Uses:
It is bactericidal mainly to gram (-) bacteria. It is neuro and nephrotoxic
especially when given parentrally (restricted in uses). It is used orally
against diarrhea due to E. coli and shigella species.
Mode of action:
Colistin causes destruction of the integrity of cytoplasmic membrane.
Colistin is polycationic and has both hydrophilic and lipophilic moieties.
These interact with the bacterial cytoplasmic membrane, changing its
permeability. This effect is bactericidal
25