Seminar onpenicillin's

Seminar onpenicillin's

By R.Ganesh

08Z41R0046IV/IV B.PHARMACY

Under the guidance

of

T. Kala Praveen sir, M.pharm.

Dept.of Pharm.chemistry.

INKOLLU-523167(Affiliated to J.N.T.University , Approved by

AICTE)

D.C.R.M PHARMACY COLLEGE

CONTENTSCONTENTS

INTRODUCTION

HISTORY

MECHANISM OF ACTION

CHEMISTRY

CLASSIFICATION

STRUCTURAL ACTIVITY RELATIONSHIP

ADVERSE EFFECTS

USES

INTRODUCTION

Penicillin is a group

of antibiotics that

are used in the

treatment of

various bacterial

infections.

Penicillin is derived

from the

Penicillium mould.

•  It can be used to treat ailments such as strep throat, spinal meningitis, gangrene, and syphilis.

• It destroys bacteria by inhibiting the enzymes responsible for the formation of the cell wall in the bacterial cells.

HISTORYPenicillin, the world's first antibiotic,

was discovered by British scientist Alexander Fleming in 1928 on accident.

 Fleming accidentally left a dish of

staphylococcus bacteria uncovered

for a few days.

He returned to find the dish dotted

with bacterial growth, apart from one

area where a patch of mold (Penicillin

notatum) was growing.

 The mold produced a substance,

named penicillin by Fleming.

 Penicillin was finally isolated by

Howard Florey and Ernst Chain.

 Fleming, Florey and Chain

received a Nobel prize in 1945.

Structure

Penicillins as well as cephalosporins

are called beta-lactam antibiotics and

are characterized by three

fundamental structural requirements:

the fused beta-lactam structure

a free carboxyl acid group

one or more substituted amino acid

side chains

The Beta-lactam structure can also

be viewed as the covalent bonding

of pieces of two amino acids -

cysteine and valine

Mechanism of actionPenicillins enter the bacteria via the

cell wall.

Inside the cell, they bind to penicillin-binding protein.

Once bound, normal cell wall synthesis is disrupted.

Result: bacteria cells die from cell lysis.

Penicillins do not kill other cells in the body.

Chemical Properties of Penicillins

The compound consists of 2

basic structures:

1. Thiazolidine Ring

2. Beta-Lactam Ring

N

NS

O

O

H

CH3

CH3

COOH

H

R

12

- site of attachment of side

chain, R, which determines

many of the antibacterial and

pharmacologic characteristics

of a derivative (Spectrum and

penicillin-resistance)

Derivatives of benzylpenicillin,

from which the methyl benzene

radical is split off by amidase

producing

6-aminopenicillanic acid, the

parent compound of

All semisynthetic penicillins.

Thiazolidine ring (A) connected to a b-lactam ring (B), to which is attached a side chain (R).

The penicillin nucleus itself is the

chief structural requirement for

biological activity;

metabolic transformation or chemical

alteration of this portion of the

molecule causes loss of all significant

antibacterial activity

CLASSIFICATION

Natural penicillins

Penicillinase-resistant penicillins

Aminopenicillins

Extended-spectrum penicillins

Natural penicillins

penicillin G, penicillin V potassium

Penicillinase-resistant penicillins

cloxacillin, dicloxacillin, methicillin,

nafcillin, oxacillin

Aminopenicillins

• amoxicillin, ampicillin, bacampicillin

Extended-spectrum penicillins

• piperacillin, ticarcillin, carbenicillin,

mezlocillin

SAR of Penicillins

N

SHH

OCOOH

NH

H

O

The presence of a carboxy group is a requirement for PBP recognition.

When esterition of it, it behaves a pro-drugThe bioavailability will be raisen.

N

SHH

OCOOH

NH

H

O

Three chiral centers are requirement for Penicillins

bioactivity

N

SHH

OCOOH

NH

H

O

Side chain can be replaced with differentR group to obtain different compounds

With broad antibacterial spectrum

Structural Activity Relationship

Position 1 – When the

sulfur atom of

the thiazolidine ring

is oxidized to

a sulfone or

sulfoxide, it improves

acid stability, but

decreases the

activity of the agent.

•  

N

S CH3

CH3

O

H

COOH

N

O

R

H

B A

1

2

3

5

4

6

7

Position 2 – No substitutions allow

at this position, any change will

lower activity. The methyl groups

are necessary

N

S CH3

CH3

O

H

COOH

N

O

R

H

B A

1

2

3

5

4

6

7

Position 3 – The carboxylic acid of

the thiazolidine is required for

activity. If it is changed to an alcohol

or ester, activity is decreased.

N

S CH3

CH3

O

H

COOH

N

O

R

H

B A

1

2

3

5

4

6

7

Position 4 – The nitrogen is a must.

 

Position 5 – No substitutions allowed.

N

S CH3

CH3

O

H

COOH

N

O

R

H

B A

1

2

3

5

4

6

7

Position 7 – The carbonyl on the Beta-

lactam ring is a must.

N

S CH3

CH3

O

H

COOH

N

O

R

H

B A

1

2

3

5

4

6

7

•  

Postion 6 – Substitutions are allowed

on the side chain of the amide.

        An electron withdrawing group

added at this position will give the

compound better acid stability

because this substitution will make

the amide oxygen less nucleophillic.•  

N

S CH3

CH3

O

H

COOH

N

O

R

H

B A

1

2

3

5

4

6

7

 

 A bulky group added close to the

ring will make the compound more

resistant to  Beta-lactamases.

 Steric hinderence provides protect

to the Beta-lactam ring.

N

S CH3

CH3

O

H

COOH

N

O

R

H

B A

1

2

3

5

4

6

7

ADVERSE EFFECTS

diarrhea that is watery or bloody;

fever, chills, body aches, flu

symptoms;

easy bruising or bleeding, unusual

weakness;

urinating less than usual or not at all;

severe skin rash, itching, or

peeling;

agitation, confusion, unusual

thoughts or behavior;

seizure (black-out or convulsions).

nausea, vomiting, stomach pain;

vaginal itching or discharge;

headache;

swollen, black, or "hairy" tongue; or

thrush (white patches or inside

your mouth or throat).

Therapeutic Uses

• Pneumococcal Infections

– Pneumococcal Meningitis

– Pneumococcal Pneumonia

• Streptococcal Infections

– Streptococcal Pharyngitis

(including Scarlet Fever)

- Streptococcal Pneumonia,

Arthritis,

Meningitis, and Endocarditis

• Staphylococcal Infections

• Meningococcal Infections

• Gonococcal Infections

• Syphilis

• Actinomycosis

• Diphtheria

• Anthrax

• Clostridia Infections

• Surgical Procedures in Patients with

Valvular Heart Disease.