AMOXICILLIN DISCOVERY DESIGN AND DEVELOPMENT

1. COLLEGE OF MEDICINE AND HEALTH SCIENCES
SCHOOL OF MEDICINE AND PHARMACY
DEPARTMENT OF PHARMACY
HUYE CAMPUS
CLASS: PHARMACY II
ACADEMIC YEAR 2016-2017

2. NO REG.NO NAMES Others
1. 215007907 MINANI Theobald
2. 216130735 MUGISHA Carmelle
3. 216126665 UWIRAGIYE Solange
4. 216074142 NIYIRORA Clementine
5. 215012997 HAGABIMANA Pierre
6. 216163242 MURIISA Moses
7. 216074991 NIYONKURU Emmanuel
8. 216351537 NDEREYIMANA Irene Fischer

3.  Objectives of this presentation are :
 introduction
To know the discovery of the Amoxicillin from its parent Penicillin ( Amoxicillin lead
compound).
To know the target of the amoxicillin and other related antibiotics (aminopenicillins)like
ampicillin, etc,…..(amoxicillin lead compound target identification)
To identify the molecular source of Amoxicillin
To know how Amoxicillin designing and why such design took place
To Know the Amoxicillin development (how and why Amoxicillin lead compound was designed
till to amoxicillin ).
Pharmacokinetics , Pharmacodynamics, Pharmacotherapy of Amoxicillin

4. 6-aminopenicillanic acid with highlightened B-
Lactam ring (red)

5. INTRODUCTION
oamoxicillin is an artificially altered (semisynthetic) variant of
penicillin (penicillin analogue or derivate), and was first made
in 1972
oAmoxicillin is a beta-lactam antibiotic active against most of
Gram positive bacteria and some Gram negative bacteria such
as cocci, etc,….
oThose bacteria are almost found as anaerobic organisms
o Notice : generally amoxicillin is a bactericidal broad spectrum antibiotic

6. The Discovery Of The Penicillin (amoxicillin
lead compound)
The discovery of
penicillin by Alexander
FLEMING who took this
photograph in 1928. The
colony of Penicillium
mold accidentally
contaminated the plate
and is inhibiting nearby
Staphylococcus aureus
growth

7. AMOXICILLIN DISCOVERY
( without penicillin(parent drug) =no amoxicillin
Lead compound identification
oTHE 6-AMINOPENICILLANIC
ACID (6APA)
Is the penicillin base unit that are
constant in all beta lactam ring based
(aminopenicillins)
Aminopenicillanic acid is the
pharmacophore group of the lead
compound, if changed the lead loose
it drug potential (penicillin)

8.  The discovery of penicillin was important because it gave doctors an effective way to
treat bacterial illnesses. Before Alexander Fleming's discovery of penicillin, bacterial
infections often caused life-altering effects and death . This was achieved by novel drug
with new bacterial target (next slide)
 Amoxicillin is a designed penicillin, which was first discovered by Sir
Alexander Fleming in 1928 when he noticed it being produced by the mould
Penicillium notatum.
 Sir Alexander Fleming, a Scottish biologist , Professor of Bacteriology at St.
Mary's Hospital in London defined new horizons for modern antibiotics
substance penicillin (1928).
 But it was not until 1928 that penicillin, the first true antibiotic was discovered .

9. PENICILLINE TARGET IDENTIFICATION
oThere are different target of the antibiotic to bacteria such DNA
,RNA etc,.. .Amoxicillin (PENICILLIN )has action of the cell
wall destruction
oIt affects the cell wall of GRAM+ and some GRAM -, and inhibit 3rd step
and last stage of cell wall synthesis .
oThe cell wall of the bacteria is made of N Glucosamine and N-acetyl
muramic acid .
oBetween the chains of peptidoglycan ,penicillin binding protein
PBP-1A connect them .
oOnce penicillin binds to PBP of bacteria hydrolyse the cell wall make end
of bacteria life by releasing its contents

10. Target identification of amoxicillin penicillin

11. Target SELECTIVITY
oThe amoxicillin (penicillin) are selectively designed for toxicity
control
oAmoxicillin Binds to PBP that find between chain of the
peptidoglycan connect them .
oHuman cell do not have the cell wall and PBP reason of not affected
oThis is the reason why amoxicillin (penicillin) do not destroy the
normal human cell and classified as an ideal antimicrobial drug

12. Target validation
The penicillin has the binding site called the
penicillin binding protein , this site are made
by the amino acid that form different bonding
to make suitable binding .
The penicillin analogue including penicillin G,
V, Ampicillin and amoxicillin form the
different number of bonding like hydrogen
bond ,ionic bond (form different
complementarity or druggability to the
receptor )hence the designing of the
penicillin to amoxicillin strengthens the
binding of amoxicillin into the site ( target
validating)

13. Amoxicillin is stable in the GIT than other aminopenicillins because the
phenol resonance is strong that benzene resonance help in protection of
the oxygen of amide beta lactam never affected by the pH change in GIT
have the large life time because
it is less polar than amoxils
this highly polar than ampicillin
because of HYDROXIDE, hence have
short lifetime and is quickly
eliminated
The design of amoxicillin
(GIT absorption and elimination)

14. Amoxicillin prodrug
o The amoxicillin have the bitter taste , hence is the big issue to administer the
children such kind of drug with the bitter and even other fear drinking drug .
o This is hydrolysis of the Amoxicillin ProD1 into Maleic anhydride and amoxicillin in
body

15. How to increase drug potency to the target
penicillin amoxicillin
• The presence of the two
enzyme
penicillinase and
Amidase
made by the bacteria make them
resistant to the antibiotic
penicillin (amoxicilin)
• Thus in designing this drug
there are many way that can be
used to make it stable
accessing the target

16. 1. Increase of potency of amoxicillin to some highly resistant
bacteria species
First there is the extension of the amoxicillin into Schiff base
will strength the resonance by phenol and more stable than
amoxicillin and H bond be strong with extended phenol

17. Secondly the Schiff base ligand is combined with the metal to form the metal complex
Structure of metal complexes
where M = Co(II) and Ni(II)
The synthesized metal complexes and the free
Schiff base ligand were screened for antibacterial
activity against pathogenic bacterial
species Escherichia coli, Staphylococcus aureus,
Pseudomonas aeruginosa

18. 2. Amoxicillin alliance
Amoxicillin has either Clavulanate Potassium or Clavulanic acid as sentry drugs
Sentry drug is the chemical substance that help in potency increase but does not exercise
the effect
Amoxicillin is extended spectrum penicillin and Clavulanate potassium or Clavulanic acid are a
β-lactamase inhibitor. Addition of Clavulanate or Clavulanic acid with amoxicillin further
extends the antimicrobial spectrum of amoxicillin against β-lactamase producing bacteria
The challenges obtained ; amoxiclav is the one most frequently associated with liver damage
and many case the patient get hospitalized but this adverse effect is recovered for short time .
The combination of amoxicillin with one of two sentry drug give Augmentin
Amoxicillin
The molecular formula is C16H19N3O5S•3H2O and the molecular weight is 419.45. The
chemical structure is: (next slide)

19. AMOXICILLIN STRUCTURE AND THE SENTRY DRUG
The clavulanic acid are
involve in inhibiting the
bacteria secreting the
penicillinase or Beta
lactamase that open the
beta lactam ring and
make bacteria resistantt
Clavulanic
acid
amoxils

20. Amoxicillin development
Semi-synthetic
penicillins can
be produced
from the 6-APA
penicillanic
base unit.

21. HOW DEVELOPMENT OF AMOXICILLIN FROM PENICILLIN
Penicillins contains β‐lactam ring as basic nucleus & this ring can be opened in neutral
or acidic solutions which can result in an inactive drug.
The ring is also acted on by β‐lactamase, which is an enzyme produced by some
bacteria that can degrade Penicillin antibiotics (said in previous slide)
Therefore, Penicillin antibiotics need to have chemical structures added to increase their
acid stability and their β‐lactamase resistance
Adding an electron withdrawing group onto the 6‐position (located on the β‐lactam
ring) amide group can increase its acid stability by making the amide oxygen less
nucleophilic.
This ensures that the amide oxygen will not be attacked and keep the β‐lactam ring's
carbonyl group not be opened

22. Penicillin G
The purpose was to make the penicillin being stable in the GIT (never
destroyed)
The main precursor are phenylacetic acid(Ph-CH2-COOH) in the
production of Penicillin G and by extension the PG was obtained

23. penicillin V
main precursor phenoxyacetic acid (Ph-O-CH2-COOH) in
the production of penicillin V. and also by extension of 6APA ,
PENICILLIN V was obtained
Penicillin V

24. Ampicillin
 In the 1950s, the entire β‐lactam family of antibiotics consisted of two compounds with a
limited spectrum of activity– penicillin G and penicillin V. There was considerable
interest in developing new penicillins by modifying the side chain of the molecule
 The free amino group on this molecule enhances activity against gram-negative bacteria
and it has broad spectrum
 One method was to provide the side chain precursors in the fermentation broth.
 The range and diversity of compounds that could be produced in this way, however, were
limited

25. Amoxicillin
• It was find that the ampicillin is unstable in the GIT and this reduce the ampicillin
bioavalabilty . This causes poor absorption of the ampicillin.
• This develop the idea of developing amoxicillin
It shows the
Amoxicillin and
Ampicillin serum
concentrations in
fasting subjects
following 500 mg
dose24

26. Amoxicillin dThis is also produced from the cleavage of penicillin G. The enzyme
penicillin acetylase cleaves the penicillin G into its two main
precursors; phenyl acetic acid and 6-APA
Or amidase

27. Penicillin acetylase (or amidase ) cleave the penicillin G or V to
obtain the 6APA
there was The extension of 6-aminopenicillanic acid with P-
hydroxyphenylglycine methyl ester

28. Pharmacokinetic ;Pharmacodynamics; Pharmacotherapy
Brand Name(s): Amoxicot, Amoxil, Biomox, DisperMox, Moxilin, Polymox, Trimox, Wymox)
Chemical Class: Penicilline derivative, aminopenicillin
Pharmacotherapy:
o Amoxicillin is used in treatment of bacterial infections like, middle ear infections ,
pneumonia , skin infections and urinary tract infections,GIT infection ect,…..
o Therapeutic Effect: Bactericidal in susceptible microorganisms.
Pharmacokinetics: Well absorbed from the GI tract. Protein binding: 20%. Partially
metabolized in the liver. Primarily excreted in urine breast milk in small quantities.
Removed by hemodialysis. Half-life: 1-1.3 hr (increased in impaired renal function) and 3.7
hrs in new born.
o Route of administration:It is taken by mouth or less commonly by injections,topical
Pharmacodynamics:
o Side effect:Side effect include:nosea, vomiting, rashes ,allergy
o Drug-drug interaction :It can interact with probenecid and reduces it’s renal
excretion,warfarin,allopurinol

29. Mechanism of Action: A penicillin that inhibits bacterial cell wall synthesis.
It acts by binding to penicillin binding protein 1A (PBP‐1A) located inside the bacterial cell wall
The penicillins (amoxicillin), acylate (addition of acyl group make irreversible bonding) the
penicillin‐sensitive transpeptidase C‐terminal domain by opening the lactam ring causing
inactivation of the enzyme, prevents the formation of across‐link of two linear peptidoglycan
strands, inhibiting the third and last stage of bacterial cell wall synthesis, which is necessary for cell
division and cell shape and other essential processes.
And tthus, the lethality of penicillin for bacteria involves both lytic and non‐lytic mechanisms
Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible
that amoxicillin interferes with an autolysin inhibitor
The imperfect cell wall synthesis make bacterial cells to absorb water by osmosis; as gram positive
& gram negative bacteria have 10‐30 & 3‐5 times intracellular osmotic pressure than external
environment and lead to cell bursting .

30. Available Forms:FORMULATION
o Capsules (Help in cover of bad odor ,reach the site of
absorption quantitatively): 250 mg (Amoxil, Biomox,
Trimox, Wymox), 500 mg (Amoxil, Biomox, Trimox).
o Powder for Reconstitution Because Amoxil is sensitive to
water due ester functional group : 50 mg/ml (Trimox), 125
mg/5 ml (Amoxil, Trimox), 200 mg/ml (Amoxil), 250 mg/ml
(Amoxil, Biomox, Trimox), 400 mg/ml (Amoxil).
o Tablets (Amoxil): 500 mg, 875 mg.

31. references
http://www.antibiotics-info.org/amoxicillin-clavunate-potassium.html
• https://www.researchgate.net/publication/281411215_ANTIBACTERIAL_ACTIVITY_OF
_NOVEL_PRODRUGS_OF_AMOXICILLIN_AND_CEPHALEXIN
• https DRUG DESIGNAmoxicillin - ScienceDirect Topics.html
• Antibiotic Drugs, Information, Mechanism of action, Pharmacokinetics and Description of
Amoxicillin.html
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