Field of Pharmacy Sciences

Bachelor of Pharmacy-PharmD (Clinical Pharmacy) Program

Medicinal Chemistry I (PMC306) Lecture 6

Mohamed Kandeel El-Ashrey, PhD 2024/11/2

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Tetracyclines
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Tetracyclines
Spectrum & Uses
Tetracyclines are broad spectrum antibiotics which also can be
used for:
• Malarial infections
• Intestinal amoebiasis & bacillary dysentery
• Acne

MOA
• Tetracyclines are PROTEIN SYNTHESIS INHIBITORS (Bacteriostatic)

• They bind to 30S ribosomal subunit → prevents binding of amino

acyl t-RNA to the mRNA- ribosome complex.

• Prokaryotes have 70S ribosomes, each consisting of

a small (30S) and a large (50S) subunit.
Selective Toxicity • Eukaryotes have 80S ribosomes, each consisting of
a small (40S) and large (60S) subunit.
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Naphthacene Octahydronaphthacene
(9 double bonds) (5 double bonds)
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3ry
Alcohol 4𝛂-dimethyl
amino

Enolic
Alcohol
Aromatic
Ring D

Phenolic OH
Ketone
Amide
Enolic
Alcohol
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In chemistry, an amphoteric compound (from Greek amphi- 'both')

Amphoteric is a molecule or ion that can react both as an acid and as a base.

4𝛂-dimethyl
amino
Basic
pKa of conj. Acid = 9.7

Acidic
Amide pKa = 3.3
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Chelation (metal binding properties)

Ketone and alcohol can chelate metal ions → Insoluble non-absorbable chelate

Tetracyclines should not be concomitantly taken with metal products:

• Milk and milk products [Ca]

• Antacids [Mg and Al]
• Hematinic products [containing Fe]
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Chemical Instability
Epimers: two isomers differ in configuration
A. Acidic pH (2-6); Epimerization at only one chiral [asymmetric] center

α-configuration β-configuration

4-Epitetracycline
Inactive
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Chemical Instability

B. Strongly acidic pH (1-2); Dehydration & Aromatization

C C

Anhydrotetracycline

Inactive
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Chemical Instability

B. Strongly acidic pH (1-2); Dehydration, Aromatization & Epimerization

Inactive

Nephrotoxic

Fresh and Stored tetracyclines are

tested for this product

4-Epianhydrotetracycline
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Chemical Instability

C. Basic pH; Lactonization

Isotetracycline
Inactive
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Natural vs Semisynthetic Tetracyclines

Natural Tetracyclines
Unstable to strong acids and bases
with 6-OH

Semi-synthetic Tetracyclines Stable to strong acids and bases

without 6-OH
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Natural Tetracyclines

Tetracycline

• Oral
• Low cost
• Unstable (why?)
• Used for Acne
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Natural Tetracyclines

7-Cl increases
Chlortetracycline lipophilicity & activity

Oral & Topical

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Natural Tetracyclines

Oxytetracycline 5-hydroxyl group increases

hydrophilicity

Topical (eye or skin ointment)

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Semisynthetic Tetracyclines

Doxycycline

Compared to tetracycline structure:

• It has 5-hydroxyl group.
• 6-hydroxyl group is absent.

• Used orally.
• Has less GIT disturbances.
• In patients with uremia or significantly impaired kidney function, doxycycline is often a preferred
tetracycline antibiotic because it undergoes hepatic rather than renal elimination. Unlike other
tetracyclines, doxycycline’s excretion does not heavily rely on the kidneys, so it doesn’t accumulate to
toxic levels in uremic patients.
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Semisynthetic Tetracyclines

Doxycycline
Semi-synthesis

H2

DMF
[Dimethylformamide]
oxytetracycline Doxycycline
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Aminoglycosides
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Aminoglycosides
Glycosides of Amino Sugars

Sugar Part Non-Sugar Part

[Glycone] [Aglycone]
Glycosides
Sugar Part Non-Sugar Part
[Glycone] [Aglycone]

Glycosidic Bond
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Sugar Part (Glycone)

Example: D-Glucose

Open Chain Form Cyclic Hemiacetal Form

Fischer Projection Haworth Projection
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Non-Sugar Part (Aglycone) Guanidine

Streptidine
Streptamine

2-Deoxy
Streptamine

Spectinamine
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MOA Protein Synthesis Inhibitors

• Highly hydrophilic, enter the cells through active transport

• Binds to 30 S ribosomal subunit → Misreading of genetic code
leading to formation of (nonsense/misfolded protein) →
destruction of the semi-permeability of the membrane →
Bactericidal
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They are antibiotics obtained from :
Aminoglycosides 1. Streptomyces species [end with suffix mycin].
2. Other species [Micromonospora] [end with suffix micin].

Spectrum & Uses

• Broad Spectrum Antibiotics
• Only effective against aerobic bacteria [anaerobic bacteria lack respiration-
driven active transport process]
• Used Orally for GIT infection [why?]
• Streptomycin used I.M. for T.B.
• Tobramycin is effective in Pseudomonas aeruginosa infections.

Toxicity (limited use)

1. Nephrotoxicity: they accumulate in the renal proximal tubule cells, where
they induce oxidative stress, mitochondrial dysfunction, and cell damage,
leading to acute kidney injury (AKI).
2. Ototoxicity: they accumulate in the inner ear, particularly in the cochlear
and vestibular cells, causing cellular damage. This damage is often linked
to free radical formation and apoptosis in hair cells of the ear.
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(1) Streptidine Derivatives

Streptomycin

1943: Isolated by fermentation of Streptomyces griseus

Streptomycin was the first effective drug against T.B.

Selman Waksman
Nobel Prize in Medicine 1952
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Used for tubercular

Streptomycin infections [in combination]

Streptidine
[Aglycone]

N-methyl Glucosamine
[amino sugar]

Streptose
Aldehyde Group [Neutral sugar]
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(2) 2-Deoxy Streptamine Derivatives

Sugar Sugar
Kanamycin

2-Deoxy Streptamine

Kanamycin A

Due to its toxicity and resistance concerns, kanamycin is typically reserved for
situations where other antibiotics are ineffective.
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Kanamycin Bacterial Resistance
R-factors are plasmids that carry genes encoding for enzymes that confer resistance to various
R-Factor Mediated Enzymes antibiotics, including kanamycin. These enzymes are typically aminoglycoside-modifying
enzymes, and they alter kanamycin's structure, preventing it from binding to bacterial
ribosomes and inhibiting protein synthesis.
Ph

1. Acetyl transferases: make N or O-acetylation. Ac Ad

2. Adenyl transferases: make O-adenylation .
3. Phosphotransferases: make O-phosphorylation.

This gives metabolites that are

incapable of binding to ribosomes
Ac Ad

Ac
Ac
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(2) 2-Deoxy Streptamine Derivatives

(am i kay' sin)

Amikacin
Decreased resistance by Steric Effect

↓ Affinity to 4-Amino-2-Hydroxy Butyric Acid group [AHBA]

inactivating enzymes Steric Effect
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(2) 2-Deoxy Streptamine Derivatives

Tobramycin
Decreased resistance by Absence of
targeted functional group
Used parenterally for Pseudomonas
infections.
Used by inhalation for Pseudomonas
infections in cystic fibrosis patients
[this route decreases toxicity]

Broader spectrum > Kanamycin

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(2) 2-Deoxy Streptamine Derivatives

Gentamicin
Decreased resistance by
Absence of targeted functional group
Used parenterally for
Pseudomonas infections
[Pneumonia, Urinary Tract
Infections UTI]

Used topically for Pseudomonas

infections [Bruns]

Broader spectrum
> Kanamycin
 Incompatibility of aminoglycosides with 𝛃–lactam antibiotics 31

• Beta-lactams and aminoglycosides are commonly used

together to achieve synergistic effects, especially in
treating severe Gram-negative bacterial infections.
• However, they are chemically incompatible when mixed
in the same solution or administered through the same
intravenous (IV) line.
• This incompatibility is due to chemical reactions
between the two drug classes, primarily involving the
breakdown of the beta-lactam ring, which is essential
for the antibacterial activity of beta-lactams.

Consequences
Loss of Efficacy: The inactivation of the beta-lactam antibiotic leads to reduced antibacterial activity,.
Reduced Aminoglycoside Potency: The aminoglycoside may also lose some of its effectiveness due to chemical interaction.

Recommendations for Use

To avoid incompatibility:
Administer Separately: Beta-lactams and aminoglycosides should not be mixed in the same syringe or IV line. Instead, they
should be administered sequentially or in separate lines.
Flush IV Lines: If the same IV line must be used, flush it with saline between administering each drug to prevent contact in the
line.
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(3) Spectinamine Derivatives
Spectinamine
Spectinomycin

It is given by intramuscular injection to treat gonorrhea,

especially in patients who are allergic to Penicillins.

Differ in MOA than other aminoglycosides:

• It inhibits tRNA translocation in ribosomes Unusual Three Fused Rings

NOT causing incorporation of wrong amino
acids into peptide chain.
• It’s Bacteriostatic
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Chloramphenicol
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Chloramphenicol

It has two chiral centers (four isomers),

D-Threo isomer is the active
2,2-dichloro-N-((1R,2R)-1,3-dihydroxy-1-
(4-nitrophenyl)propan-2-yl)acetamide

MOA Protein Synthesis Inhibitors

Binds to 50 S ribosomal subunit [Selective] → Interfere with

peptidyl transferase action → Block attachment of amino
acids to nascent peptide chain

Bacteriostatic
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Spectrum & Indications

• Broad spectrum antibiotic.

• Effective in meningitis, typhoid and anaerobic infections.
• Mostly used as eye drops for ophthalmic infections

Adverse Effects

1. Bone marrow depression: fatal aplastic anemia.

2. Grey baby syndrome: when give in the first week after birth
[undeveloped metabolic functions leading to its accumulation]
3. Inhibition of hepatic mixed functional oxidases: drug-drug interactions.
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Prodrugs for Chloramphenicol Esters of the hydroxyl group at C3

Chloramphenicol Palmitate
Form: Oral suspension (commonly used for pediatric
formulations).
Purpose: Designed to improve palatability and
stability for oral use. Chloramphenicol palmitate is
insoluble in water, making it less bitter and better
suited for children.

Chloramphenicol Hemisuccinate

Form: Injectable (intravenous administration).

Purpose: Developed to increase water solubility for injection, as
chloramphenicol itself has low solubility in water.