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

structure2. Give properties of an ideal antibiotic.3. Give general properties of an antibiotic.4. Discuss different basic structures of antibiotic

classes.

Classification by Chemical structure1. Beta-lactam (Penicillins, Cephalosporins,

monobactam, clavulanic acid)2. Aminoglycosides3. Tetracyclines4. Macrolides5. Polypeptides6. Chloramphenicol7. 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 toxicity5. Cost effective

General Properties

1. Grouped in classes based on their chemical structure.

2. Members of the class share characteristicsi. Clearanceii. Mechanism of actioniii. Absorptioniv. Side effects

3. Elicit various types of allergic reactions4. 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. (3162-

3167)• 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.

• β-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-1-azabicyclo 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 semisyntheticpenicillins.

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 β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, and methicillin.

– Another development was the antipseudomonalpenicillins, 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 stearichindrance 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 beta-lactamase, 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 β-lactamase resistance, since they are relatively intolerant of side-chain sterichindrance.

• able to bind to penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but not inactivated by β-lactamases.

Dicloxacillin

Flucloxacillin

• The presence of the isoxazolyl group on the side-chain of the penicillin nucleus facilitates the β-lactamase resistance, since they are relatively intolerant of side-chain sterichindrance.

• able to bind to penicillin-binding proteins (PBPs) and inhibit peptidoglycan crosslinking, but not inactivated by β-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 β-lactamantibiotics.

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