These slides discuss about medicinal chemistry of penicillin antibiotics.

1. PENICILLINS

2. Historical Background
Penicillin:Penicillin was the world’s first antibiotic and was discovered bySir Alexander Fleming in 1928
accidently.
Alexander Fleming, noticed that one of his experimentalcultures of Staphylococcus was contaminated with
mould,which caused the bacteria to lyse. Since mould belongedto the family Penicillium, he named the
antibacterialsubstance penicillin.
On Friday, September 28, in 1928, Fleming left the lid off ofone of his Petri dishes for several weeks, and a
fungal sporelanded on it. After returning from vacation, Fleming noticedthat his Staphylococcus (bacteria)
culture was contaminatedwith this fungus which cause the bacteria to die. He thencarefully examined it
first.

3. Then, he grew a pure culture and discovered that it was a Penicilliummould, now known to be Penicillium
notatum.
He concluded that Penicillium mould must be secreting anantibacterial substance, which he isolated first in
crude form ofthe active substance and named it as penicillin.
Unfortunately, the substance was also unstable and Flemingwas unable to isolate and purify the
compound.Florey and Chain in 1938 by using processes such as freezedryingand chromatography which
allowed isolation of pure formof penicillins.
Fleming, Florey, and Chain shared the 1945 Nobel Prize for theirmedicinal work on the antibiotic
penicillin.

4. Penicillins are called beta-lactam antibiotics and arecharacterized by three fundamental structural
requirements:
A) Beta-lactam ring
B) Thiazolidine ring
C) Side chains (R)

5. Classification
1. Natural Penicillins: Natural penicillins, the first agents in the penicillin family, are obtained directly
from the Penicillium mouldand do not require further modification. e.g., Penicillin G.
2. Semisynthetic Penicillins
(i) Acid resistant penicillins
(ii) Penicillinase resistant penicillins
(iii) Extended spectrum penicillins
(a)Aminopenicillins
(b)Carboxypenicillins
(c) Ureidopenicillins
(d)Amidinopenicillins

6. Natural penicillins
Penicillin G (Benzyl penicillin) Penicillin F Penicillin K
Penicillin N Penicillin O Penicillin X

7. Semisynthetic penicillins
These penicillins are produced by chemically combining specific side chains in place of benzyl side chain of
Penicillin G.
(i) Acid resistant penicillins
Penicillin V Phenethicillin Propicillin

8. (ii) Penicillinase resistant penicillins (Anti-staphylococcal penicillins)
Oxacillin Cloxacillin Dicloxacillin
Flucloxacillin Methicillin Nafcillin

9. (iii) Extended spectrum penicillins
(a) Aminopenicillins
Ampicillin Amoxycillin Epicillin
Bacampicillin Pivampicillin

10. (b) Carboxypenicillins
Carbenicillin Carfecillin Carindacillin
Ticarcillin Temocillin

11. (c) Ureidopenicillins
Azlocillin Mezlocillin Piperacillin
(d) Amidinopenicillins
Mecillinam Pivmecillinam

12. Mechanism of action
Penicillin blocking the construction of bacterial cell wall by binding with penicillin binding protein and thus
weakening and causing break of cell wall, finally killing the bacteria.
Inhibit the synthesis of peptidoglycon layer containing NAM &NAGconnected by penicillin binding
proteins(PBP).
Transpeptidases locatedwithin the cell membraneare responsible forcross linking the peptidoglycan chains
of cell wall.
Penicillins inactivatethe transpeptidase (PBP) enzymeby covalently bondingto the serine residueswithin the
active site.

15. In absence of penicillins

16. In presence of penicillins

17. https://www.youtube.com/watch?v=sEaMnZmPJLI

18. THERAPEUTIC USES
 Skin & soft tissue infections.
 Diphtheria, tetanus, gas gangrene.
 Intra
-abdominal infection, syphilis.
 Ear, nose, lungs infections.
 Streptococcal infections.
 Drug of choice for Anthrax,Trench mouth, Rat bite fever,Actinomycosis

19. STRUCTURE ACTIVITY RELATIONSHIPS

24. CHEMICAL DEGRADATION

28. ADVERSE EFFECTS
Diarrhea that is watery or bloody;
 Fever, chills, body aches, flu symptoms;
 Urinating less than usual or not at all;
 Severe skin rash, itching, or peeling;
 Agitation, confusion, unusual thoughts or behavior; or
 Seizure (black
-out or convulsions).
 Vomiting , Nausea and Stomach pain.
 Headache
 Thrush( white patches inside mouth or throat)