Contents

• Structures of different tetracyclines

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• SAR of tetracyclines

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o Ring A

Ph
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o Ring b
tB
as
o Ring C
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Faculty of Pharmacy © Ramaiah University of AppliedSciences
 Learning Objectives

At the end of this lecture, student will be able to

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• Name some examples of tetracyclines

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Ph
• Explain the SAR of tetracyclines

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 Minocycline Hydrochloride

• 7-dimethylamino-6-demethyl-6-deoxytetracycline

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ac
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• The most potent tetracycline currently used in therapy

ar
Ph
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• Minocycline is well absorbed orally to give high plasma and tissue

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tB
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levels
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 Facts
• Stable chelate complexes are formed by the tetracyclines with many
metals, including calcium, magnesium, and iron

.in
• Such chelates are usually very insoluble in water

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ac
m
• Impaired absorption of most tetracyclines in the presence of

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Ph
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milk,calcium ,magnesium ,aluminum-containing antacids and iron

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tB
salts as
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• Soluble alkalinizers, such as sodium bicarbonate, also decrease the

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GI absorption of the tetracyclines

• Deprotonation of tetracyclines to more ionic species and the

observed instability of these products in alkaline solutions 4
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 Facts
• The affinity of tetracyclines for calcium causes them to be
incorporated into newly forming bones and teeth as tetracycline–

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calcium orthophosphate complexes

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ac
m
• Deposits of these antibiotics in teeth cause a yellow discoloration

ar
Ph
that darkens (a photochemical reaction) over time

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tB
• Tetracyclines are distributed into the milk of lactating mothers
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And will cross the placental barrier into the fetus.

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• Effects of these agents on the bones and teeth of the child should
be considered before their use during pregnancy or in children

younger than 8 years of age 5

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 Structure–Activity Relationships

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ac
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Ph
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tB
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 SAR Contd…

• All derivatives containing fewer than four rings are inactive or

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nearly inactive

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• The integrity of substituents at carbon atoms 1, 2, 3, 4, 10, 11, 11a,

Ph
ch
• And 12, representing the hydrophilic “southern and eastern”

en
tB
as
• Faces of the molecule cannot be violated drastically
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• Without deleterious effects on the antimicrobial properties of the

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resulting derivatives

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 Ring A

• Modified only slightly without dramatic loss of antibacterial

potency

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ac
• The enolized tricarbonyl methane system at C-1 to C-3 must be

m
ar
intact for good activity

Ph
ch
en
• Replacement of the amide at C-2 with other functions (e.g.,
tB
as
aldehyde or nitrile) reduces or abolishes activity
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• Monoalkylation of the amide nitrogen reduces activity

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proportionately to the size of the alkyl group

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 Ring A Contd…
• Aminoalkylation of the amide nitrogen, accomplished by the
Mannich reaction yields derivatives that are substantially more
water soluble than the parent tetracycline and are hydrolyzed to it

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in vivo (e.g., rolitetracycline)

ac
• The dimethylamino group at the 4-position must have α-

m
ar
orientation

Ph
ch
• 4-epitetracyclines are very much less active than the natural

en
isomers
tB
as
• Removal of the 4-dimethylamino group reduces activity
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• Activity is largely retained in the 1oand N-methyl 2o amines but

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rapidly diminishes in the higher alkylamines

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 Ring B

• A cis-A/B-ring fusion with a -hydroxyl group at C-12a is essential

.in
• Esters of the C-12a hydroxyl group are inactive with the exception

ist
ac
of the formyl ester which readily hydrolyzes in aqueous solutions

m
ar
Ph
• Alkylation at C-11a leads to inactive compounds demonstrating the

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importance of an enolizable –diketone functionality at C-11 and C-
tB
as
12
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• The importance of the shape of the tetracyclic ring system is

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illustrated further by substantial loss in antibacterial potency

resulting from epimerization at C-5a
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 Ring B Contd…

• Epimerisation at C-5aleads to loss of antibacterial potency

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• Dehydrogenation to form a double bond between c-5a and c-11a

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markedly decreases activity as does aromatization of ring C to form

Ph
ch
anhydrotetracyclines

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tB
• Substituents at positions 5, 5a, 6, 7, 8, and 9, representing the
as
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largely hydrophobic “northern and western” faces of the molecule

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can be modified with varying degrees of success resulting in

retention and sometimes improvement of antibiotic activity
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 Ring B Contd…
• A 5-hydroxyl group, as in oxytetracycline and doxycycline, may
influence pharmacokinetic properties but does not change

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antimicrobial activity

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 Ring C

• Aromatization of ring C decrease activity

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• Neither the 6-α-methyl nor 6-β- hydroxy group is essential for

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antibacterial activity

Ph
ch
• The 6-hydroxy tetracyclines have increased lipid solubility

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tB
as
• They are absorbed more completely foloowing oral administration
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 Ring D

• A variety of mono and disubstituted derivatives are prepared by

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electrophilic substitution reactions at C-7 and C-9

ac
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• Strongly electron withdrawing groups (chloro and nitro)

Ph
ch
• Strongly electron-donating groups (Dimethylamino ,minocycline)

en
tB
• C-8 has not been studied because this position cannot be
as
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substituted directly by classic electrophilic aromatic substitution

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reaction

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 Summary

• Enolized tricarbonyl system from C-1 to C-3 must be intact for good

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activity

ac
m
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• Removal of dimethyl of dimethyl amino group decreases activity

Ph
ch
• A cis A/Bring fusion with beta-hydroxy group at C-12a

en
tB
as
• Aromatisation of ring C decreases activity
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