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Pharmaceutical Chemistry (PCT 212)

UNIT 1: Antibiotics; Classification, Nomenclature


and Properties
20 Jan 2014

Learning Objectives
At the end of this lecture the learner should
be able to;
1. Classify antibiotics according to their chemical
structure
2. Give properties of an ideal antibiotic.
3. Give general properties of an antibiotic.
4. Discuss different basic structures of antibiotic
classes.

Classification by Chemical structure


1. Beta-lactam (Penicillins, Cephalosporins,
monobactam, clavulanic acid)
2. Aminoglycosides
3. Tetracyclines
4. Macrolides
5. Polypeptides
6. Chloramphenicol
7. Synthetic antibacterial agents (Sulphonamides,
Quinolones, nitrofuran compounds and
metronidazole)
8. Anti-Tb drugs

Properties of an ideal antibiotic


1. Good pharmacokinetic and
pharmacodynamic profiles
2. Should be able to kill bacteria without
causing harm to the patient. (bactericidal and
bacteriostatic)
3. Tissue penetration.
4. Less toxicity
5. Cost effective

General Properties
1. Grouped in classes based on their chemical
structure.
2. Members of the class share characteristics
i.
ii.
iii.
iv.

Clearance
Mechanism of action
Absorption
Side effects

3. Elicit various types of allergic reactions


4. Affect normal flora as well as pathogens.

General properties
5. Selective in their effect on different
microorganisms (spectrum of activity).
6. Vary in chemical structure (simple to
complex).
7. Vary in their toxicity to patients.
8. Vary in mode of action upon organisms.
9. Some are rapidly destroyed by various
bacteria while others are highly resistant to
microbial action.

Penicillins
Basic structure;
Thiazolidine ring
Beta-lactam ring
Amino-group; substituents (R) are attached to the
amino group

Can be altered by substituting side chains


Alterations
Antimicrobial spectrum
Absorption characteristics
Resistance to beta-lactamase deactivation

Penicillins
Resistance; most significant- bacterial production
of beta-lactamase
Destroys the beta-lactam ring by means of hydrolysis
Alteration of binding sides for the penicillins (PBPs)

Penicillin groups

Penicillins e.g. Penicillin G.


Aminopenicillins/ extended-spectrum penicillins.
Penicillanase-resistant penicillins.
Antipseudomonal penicillins.

Group Work/Discussion
Group 1: Structure of Cephalosporins, monobactams and
carbapenems and beta-lactamase inhibitors. (3156 3161)
Group 2: Structure of Tetracyclines and macrolides. (31623167)
Group 3: Structure of Aminoglycosides (3168 3173)
Group 4: Structure of Sulphonamides and quinolones (3174
3179)
Group 5: Structure of Antimycobacterial (3180 3184)
Look at structural modifications and how they affect;

Water solubility.
Lipid solubility.
Kinetics properties of the drug.
Pharmacodynamic activity of a drug.

Plenary report back on 27 January 2014 @ 1030am.

Pharmaceutical Chemistry (PCT 212)


Structure of antibiotics
Penicillins

23 January 2014

Penicillins
Penicillin a group of antibiotics derived from
Penicillium fungi, Examples include; penicillin
G, procaine penicillin, benzathine penicillin,
and penicillin V.
-lactam antibiotics used in the treatment of
bacterial infections caused by susceptible,
usually Gram-positive, organisms.

6-aminopenicillanic acid (6-APA)

6-Amino-3,3-dimethyl-7-oxo-4- thia-1azabicyclo heptane-2- carboxylic acid

6-aminopenicillanic acid
6-APA is the core of penicillins.
It is obtained from the fermentation brew of
the Penicillium mold.
Used as the main starting block for the
preparation of numerous semisynthetic
penicillins.

Preparation of 6-APA
6-APA can be prepared enzymatically or chemically
starting from penicillin G.
The first major development was ampicillin, which
offered a broader spectrum of activity than either of the
original penicillins.
Further development yielded -lactamase-resistant
penicillins, including flucloxacillin, dicloxacillin, and
methicillin.
Another development was the antipseudomonal
penicillins, such as carbenicillin, ticarcillin, and
piperacillin.

Preparation of 6-APA

Penicillin biosynthesis

Basic/core structure

where "R" is the variable group/side chain


that differentiates the penicillins from one
another.

Natural Penicillins
Benzyl penicillin destroyed by gastric acid
Phenoxymethylpenicillin resist acid
(improved oral absorption)

Benzylpenicillin
Commonly known as penicillin G.

destroyed by gastric acid

Phenoxymethylpenicillin
Commonly known as Penicillin V

more acid-stable than benzylpenicillin

Antistaphylococcal penicilins
Are beta-lactamase resistant
-possess an acyl side-chain to resist the action
of staphylococcal beta-lactamase, by stearic
hindrance of access of the drug to the
enzymes active sites.
Cloxacillin resists degradation by gastric acid
(improved oral absorption)
Flucloxacillin better oral absorption than
cloxacillin.

Cloxacillin
Cloxacillin is a semisynthetic antibiotic in the
same class as penicillin. Cloxacillin is used
against staphylococci that produce betalactamase, due to its large R chain, which does
not allow the beta-lactamases to bind.

Cloxacillin

Dicloxacillin
The presence of the isoxazolyl group on the
side-chain of the penicillin nucleus facilitates
the -lactamase resistance, since they are
relatively intolerant of side-chain steric
hindrance.
able to bind to penicillin-binding proteins
(PBPs) and inhibit peptidoglycan crosslinking,
but not inactivated by -lactamases.

Dicloxacillin

Flucloxacillin
The presence of the isoxazolyl group on the
side-chain of the penicillin nucleus facilitates
the -lactamase resistance, since they are
relatively intolerant of side-chain steric
hindrance.
able to bind to penicillin-binding proteins
(PBPs) and inhibit peptidoglycan crosslinking,
but not inactivated by -lactamases.

Flucloxacillin

better oral absorption than cloxacillin.

Broad spectrum penicillins


Aminopenicillins
Developed for gram-negative antimicrobial
activity.
Amoxycillin structural analogue of Ampicillin,
improved oral absorption, greater bioavailability
and fewer adverse effects.
Ampicillin acid stable

Amoxycillin

better-absorbed, following oral


administration, than other -lactam
antibiotics.

Ampicillin

offered a broader spectrum of activity than


either of the original penicillins.

Antipseudomonal Penicillins
Carboxypenicillins (same antibacterial
spectrum as Ampicillin and susceptible to
beta-lactamase)
Ticarcillin
Carbenicillin

Ureidopenicillins
Piperacillin -

Carboxypenicillins
TICARCILLIN

Carbenicillin

Carbenicillin is more stable at lower pH than


ampicillin.

Ureidopenicillins
PIPERACILLIN
is an extended spectrum beta-lactam antibiotic of
the ureidopenicillin class.
It is normally used together with a beta-lactamase
inhibitor, notably in the combination
piperacillin/tazobactam.

Piperacillin

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