Transcript Tetracycline

Lecture 4
Medicinal Chemistry 1
PC 509
Prof. Dr/ Ghaneya Sayed Hassan
[email protected]
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Non -lactam antibiotics
Tetracyclines
Obtained from :
(1) Fermentation procedures from Streptomyces species.
(2) Chemical transformation of natural products.
8
9
7
6
D
C
10
11
5a
5
4a
11a
12
4
A
B
12a
H3C
3
CH3
OH
2
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Octahydronaphthacene
[5 double bonds]
2
HO
N
CH3
OH
O
OH
OH
CONH2
O
Uses:
1-Bacteriostatic broad spectrum antibiotic [effective ≠ G+ve , G-ve bacteria ,
Rickettsiae, Mycoplasma, Chlamydia & Cholera].
2- Acute intestinal amoebiasis.
3- Plasmodium falciparum infections that are resistant to anti-malarial drugs.
4- Bacillary dysentery.
5- Tetracyclines are used to treat acne [due to activity against the bacteria on the
skin that cause acne (Propionibacterium acnes) & their lipases which promote
inflammatory changes]
(at a dosage of 250–500 mg four times a day for usually six to eight weeks at a
time, but alternatives should be sought if no improvement occurs by three months)
Mechanism of action: Specific inhibitor of bacterial
protein biosynthesis by binding to the 30S ribosomal
subunit in the mRNA translation complex
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Resistance: by making the drug unable to penetrate cell wall.
Adverse effects :
(1) Gastric discomfort [from irritation of gastric mucosa]
(2) Deposition in bone & teeth during calcification in growing children
[due to chelation with Ca++]  discoloration & hypoplasia of teeth.
(3) Hepatotoxicity.
(4) Phototoxicity: severe sunburn when patient receiving tetracycline is
exposed to sun or UV rays.
(5) Super infections: overgrowth of Candida in vagina or resistant
Staphylococci in intestine.
(6) Outdated tetracycline may produce renal damage.
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Chemical properties:
 Derived from Octahydro Naphthacene ring system:
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9
7
6
D
C
10
11
5a
5
4a
A
B
11a
12
4
12a
3
2
1
Octahydronaphthacene
[5 double bonds]
Naphthacene ring
[9 double bonds]
They are amphoteric substances: [form salts with acids or bases].
They are with 3 pka values:
H3C
HO
CH3
[3] pka2 = 7.5
[Neutral]
OH
O
[extending enone system : C10-C12]
5
OH
N
CH3
[1] pka3 = 9.7
OH
OH
[Basic]
[Amonium cation moeity]
CONH2 [2] pka1 =3.3
O
[Acidic]
[conjugated trione system]
►Commercially available tetracyclines are relatively
water-soluble HCl salts.
Tetracycline
H3C
HO
OH
CH3
O
OH
N
CH3
OH
OH
CONH2
O
4--dimethyl amino-1,4,4a,5,5a,6,11,12a-octahydro3,6,10,12,12a-pentahydroxy-6-methyl-1,11- dioxo-2Naphthacene Carboxamide.
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Chemical stability of Tetracyclines
[1] Action of acids :
→Dehydration [at C6] followed by Aromatization of ring C
► Occur in presence of strong acids pH < 2 [stomach acidity]: [for
tetracyclines with 6-OH in the form of tertiary alcohol]
► Dehydration by removal of 6-OH [if 3ry OH] → double bond formation
between C5a & C6 Aromatization of ring C → Naphthalene
derivative: Anhydrotetracycline [inactive]
► If tetracycline with 2ry 6-OH → more stable ≠ dehydration.
C
CH3
CH3
CH3
H
HO
B
H+
- H 2O
O
OH
Tetracycline
[active]
7
O
O
H
OH
O
[inactive]
Andydrotetracycline
[ring C become aromatic]
[2] Epimerization: [at C4]
Occur at intermediate pH [pH= 2 – 6 i.e. weak acidity] especially in solutions.
Leads to formation of 4-Epitetracycline [with ß-configuration] →Inactive.
[alpha]
4α
H
4ß
H+
N(CH3)2
OH
O
O
Tetracycline
[active]
+ H+
H
OH
- H+
NH2
OH
N(CH3)2
+
+H
O
N(CH3)2
OH
- H+
NH2
OH O
[beta]
NH2
OH
O
O
4-Epitetracycline
[inactive]
Presence of Epitetracycline is not recommended for two reasons:
1- Epitetracycline is inactive. So, capsules are overfilled by about 15% excess
during manufacture to give longer half life.
2- Dehydration in acidic medium → 4-Epianhydrotetracyclines [which is
nephrotoxic degradation product].
So, commercial tetracyclines products must be tested for the presence of 4Epianhydrotetracycline.
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H3C
OH
H3C
H
N
CH3
H
CH3
OH
H3C
N
CH3
H
H+
OH
NH2
OH
O
OH
OH
O
NH2
O
OH
OH
OH
O
H3C
H3C
H
N
CH3
H
O
Anhydrotetracycline
[inactive]
Tetracylcine
[active]
OH
O
CH3
OH
H3 C
N
H+
CH3
H
OH
NH2
OH
O
OH
OH
O
4-Epitetracycline
[inactive]
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O
NH2
OH
OH
O
OH
O
O
4-Epianhydrotetracycline
[inactive + renal toxic]
[3] Action of bases :[Base-catalyzed instability] : = Lactonization
 Strong bases → cleavage of ring C in tetracyclines having 6-OH →
Isotetracycline [lactonic product] which is inactive.
H3C
OH
H3C
H
N
CH3
H
H3C
OH
OH
H3C
H
N
CH3
H
OH
O
OH
OH
Tetracylcine
[active]
O
O
OH-
OH
O
O
OH
O
O
H3C
H
CH3
H
OH
OH
O
NH2
O
OH
O
Isotetracycline
[inactive]
Tetracyclines with no 6-OH :
1- Resist actions of acids & bases.
2- Higher lipid solubility & so, better absorption.
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N
O
NH2
NH2
OH
CH3
O
[4] Chelation & Incompatibility
(1)- Tetracyclines form chelation by forming insoluble non-absorbable salts in GIT
with poly valent metal ions [as Fe+2, Ca+2, Mg+2, Al+3].
They are incompatible with :
►Milk : by chelation with Ca+2 ↓ absorption of tetracyclines & ↓ absorption of Ca+2
►Antacids : as Mg(OH)2 & Al(OH)3.
►Anti-anemics [agents with Fe+2].
So, to avoid that take ion preparation 1 hr before or 2 hrs after taking tetracyclines.
(2)- They are painful upon I.M. injection: due to chelation with Ca+2 present in
muscles →insoluble complex → precipitation → pain & irritation.
So, to solve this problem.
Add EDTA to injectable product [to form water soluble complex with Ca+2 & so, no
available Ca+2 for chelation].
Buffer solution at acidic pH [chelation is less & water solubility of the complex ↑↑]
(3)- They are not recommended for pediatrics or children: this is due to chelation
with Ca+2 making insoluble complex that precipitate in teeth making dark colored
teeth & deprive bones & teeth from Ca+2.
Tetracyclines is not given to children 6-12 years (discoloration for
teeth), pregnant or lactating mothers.
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CH3
H3C
CH3
H
OH
N
Insoluble inactive complex
2+
Ca
OH
H3C
H
H3C
2+
or Fe
N
NH2
or Al
cid
a
g
on
r
t
<2
s
H
p
CH3
H
OH
NH2
OH
OH O
OH O
OH OH
3+
O
Tetracylcine
[active]
weak acid
pH 2-6
OH
OH O
O
Andydrotetracycline
(inactive)
H3C
OH
H
H3C N CH3
H
OH
OH
OH O
OH O
NH2
O
Epitetracylcine
(inactive)
strong base
CH3
H3C
H
N
CH3
H
OH
O
OH
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O
CH3
H3C
NH2
O
OH
O
CH3
H
OH
NH2
O
Isotetracycline
[inactive]
N
OH OH O
OH
O
O
4-Epianhydrotetracycline
[inactive + renal toxic]
SAR:
4 linear rings are essential
* Derivatives with < 4 rings are inactive.
* Opening of rings or aromatization of additional rings give inactive compounds.
Hydrophobic region [C5-C9]
6 alpha-methyl & 6 betaOH are NOT essential
strong e-withdrwaing group at C7
enhance activity [as Cl , NO2] OR
strong e-donating group [as dimethyl
amino] : increase activity
4-alpha dimethyl amino is essential
for activity that it forms zwitterion
which is for optimum distribution
removal of 5-OH : give 5-deoxy
compound [not affect activity]
H3C
7
8
6
5
N
H
4
H
9
11
OH
O
NH2
1
OH
OH
OH
3
2
12
10
Protonated dimethyl amino enhance activity
CH3
O
Phenoldiketone moeity is essential
Conjugation between C10-C12 is essential
O
Presence of enolized tricarbonylmethan
system at C1-C3 is essential for activity
Carbonyl gp of amide at C2 is essential.
one amide H atom may be
replaced , but if both; inactive
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H3C
N
H
CH3
OH
H
OH
O
NH2
OH
OH
O
O
Sancycline
 Pharmacophore of this group is Sancycline [it’s with
full biological activity but clinically Not important
antibiotic].
Classes of Tetracyclines [I] Natural Tetracyclines
Tetracycline
H3C
OH
H3C
H
N
CH3
H
OH
NH2
OH
O
OH
OH
O
O
(1) Produced by fermentation of Streptomyces aureofaciens OR by
catalytic reduction of chlorotetracycline.
(2) Most widely used in tetracyclines, cheap antibiotic.
(3) Its blood level after oral administration is irregular; due to inactivation
by acidic medium in stomach or basic medium in intestine.
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(4) The drug of 1st choice in ACNE.
Chlorotetracycline
►Isolated from Streptomyces
aureofaciens.
7-chloro is e-withdrawing group that 
activity.
►It’s used as chlorotetracycline HCl orally
as CAPSULES to avoid bitter taste. & may
be administered parentrally [I.V].
Cl
OH
CH3
OH
O
H3C
OH
OH
N
CH3
H
OH
CONH2
O
Demeclocycline
►Produced by fermentation of mutant
strain of Streptomyces aureofaciens.
►It lacks 6-methyl of tetracycline 
present as 2ry alcohol  more stable
> tetracycline & chlorotetracycline to
both acids & bases.
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Cl
OH
OH
O
H3C
OH
OH
N
CH3
H
OH
CONH2
O
Oxytetracycline[Terramycin®]
H3C
OH
OH
O
H3C
CH3
OH
N
H
OH
OH
OH
CONH2
O
Produced by fermentation of Streptomyces rimosis & other soil m.o.
The most hydrophilic tetracycline.
**Note that:
(1) All tetracyclines concentrate in liver  part metabolized &
conjugated to form soluble glucuronides.
(2) Most tetracyclines  reabsorption in intestine & enter urine by
glumerular filtration.
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[II] Semi-synthetic Tetracycline
Methacycline
CH2
OH
O
H3C
CH3
OH
N
H
OH
OH
OH
CONH2
►Produced by chemical modification of
Oxytetracycline.
►Removal of 6-OH   stability ≠ acids
& bases  longer serum t1/2
►The chemical precursor for Doxycycline.
O
Doxycycline [Vibramycin®]
H3 C
OH
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H
O
H3C
CH3
OH
N
H
OH
OH
OH
CONH2
O
1- One of the most important of current tetracyclines.
2- Its metabolite is preferentially excreted via bile into
faces
3- Can be given to uremic patients with infections
outside urinary tract. It causes  GIT disturbance.
►Minocycline is the most lipid-soluble of
the tetracycline-class antibiotics, giving it
the greatest penetration into the prostate
and brain.
►But also the greatest amount of central
nervous system (CNS)-related side effects,
such as vertigo .
Minocycline
H3C
N
OH
H3C
CH3
O
OH
N
OH
CH3
H
OH
CONH2
O
Semi-synthesis: From Demeclocycline
Cl
H3 C
OH
OH
O
OH
N
OH
CH3
H
H3C
OH
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N
OH
CH3
CONH2
O
O
H3C
OH
OH
Minocycline
CH3
H
catalytic reduction
OH
O
Demeclocycline
H3 C
N
OH
OH
OH
CONH2
O
Sancycline
N
Nitration
CH3
H
NO2
OH
CONH2
O
H3C
N
reductive methylation
HCHO
OH
O
OH
OH
CH3
H
OH
CONH2
O
Synthesis of Doxycycline:
[1] From Methacycline:
By direct reduction, but  give two isomers  &  [isomer with -oriented
methyl is more active 3 times > -isomer].
CH2
OH
O
H3C
CH3
OH
N
H
OH
OH
OH
reduction
alpha and beta-doxycycline
CONH2
O
[2] From Oxytetracycline HCl:
By catalytic hydrogenation in water / Dimethyl Fomramide [DMF] at
pH 1.8
H3C
OH
H3C
CH3
OH
N
H
CH3
OH
. HCl
OH
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O
OH
OH
CONH2
O
H3C
CH3
OH
N
H
H2
H2O / DMF
OH
O
OH
OH
OH
CONH2
O
Doxycycline
[3] From Benzyl mercaptan derivative of Methacycline:
By reduction with Raney Nickel
CH2
OH
O
H3C
CH3
OH
N
H
HO
OH
S
SH
CH2
OH
H3C
CH3
OH
N
H
CONH2
O
OH
OH
OH
O
CH3
H3 C
CH3
OH
N
H
CONH2
O
OH
H2 / Raney Ni
OH
O
OH
OH
CONH2
O
Doxycycline
20
OH
Protetracyclines = Rolitetracycline
Formed by condensation of Tetracycline + Pyrrolidine + Formaldehyde in
presence of t-butyl alcohol. [Mannich Reaction]
H3C
OH
OH
H3C
N
CH3
OH
O
OH OH O
CONH2
N
H
H3C
OH
H3C
N
CH3
OH
HCHO
CO
OH
Rolitetracycline
O
OH OH O
NH
CH2 N
1- It’s a Prodrug for tetracycline.
2- Highly water soluble & suitable for oral & parentral administration.
3- Activated by spontaneous decomposition NOT by action of amidase.
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Amadacycline, Omadacycline
(PTK 0796)
H3C
N
H3C
CH3
H
H3C
H3C
H
N
C
C
H2
OH O
N
H
OH
OH O
CH3
H
OH
CONH2
H3C
Phase III started. Published on Monday, July 20, 2015
Clinical trial: Phase III Study to Compare the Safety and
Efficacy of PTK-0796 in Patients with Complicated Skin
and Skin Structure Infection (CSSSI).
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According to duration of action:
1- Short-acting (Half-life is 6-8 hrs)
Tetracycline
Chlortetracycline
Oxytetracycline
2- Intermediate-acting (Half-life is ~12 hrs (
Demeclocycline
Methacycline
3- Long-acting (Half-life is 16 hrs or more), allowing to
be used one or twice daily only
Doxycycline
Minocycline
Tigecycline
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