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B Pharm VI Sem MEDICINAL CHEMISTRY – III (Theory) BP601T UNIT – I

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DOI: 10.13140/RG.2.2.14317.31204

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BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

UNIT – I: Antibiotics
Historical background, Nomenclature, Stereochemistry, Structure activity relationship, Chemical degradation
classification and important products of the following classes.
β-Lactam antibiotics: Penicillin, Cepholosporins, β- Lactamase inhibitors, Monobactams

GENERAL CONSIDERATIONS OF ANTIMICROBIAL THERAPY

An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of
antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment
and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of
antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the common
cold or influenza; drugs which inhibit viruses are termed antiviral drugs or antivirals rather than antibiotics.
▪ Basis of Antimicrobial Action
Various antimicrobial agents act by interfering with
(1) Cell wall synthesis,
(2) Plasma membrane integrity,
(3) Nucleic acid synthesis,
(4) Ribosomal function, and
(5) Folate synthesis.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 1|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

❖ Penicillin
- Penicillin (PCN or pen) is a Beta-lactam antibiotics and are used in the treatment of bacterial infections
caused by susceptible, usually Gram-positive, organisms
- In 1929 Sir Alexander fleming a physician and clinical microbiologist isolated the penicillin from the
spores of fungi (Penicillium notatum, now it is named as Penicillium chrysogenium).
- Penicillin antibiotics which are effective against many previously serious diseases such as syphilis and
Staphylococcus infections. The term "penicillin" can also refer to the mixture of substances that are
naturally, and organically, produced.
- The term "penam" is used to describe the core skeleton of a member of a penicillin antibiotic. This skeleton
has the molecular formula R-C9H11N2O4S, where R is a variable side chain.
- Structure of penicillin: The skeleton of the molecules are derived from the amino acid cysteine and valine
(from amino acid metabolism path way)

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 2|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

✓ Chemistry:
- Penicillin is a yellow brown or red amorphous powder that was so unstable that refrigeration was required
to maintain potency for even a short time.
- The crystalline penicillin must be protected from moisture but when kept dry, the salt remains stable for
year without refrigeration. The sodium and potassium salts of most of the penicillin are water soluble and
readily absorbed when given by injection or orally.
- The treatment of the penicillins with strong mineral or HgCl2 causes break down of the molecules to
PENICILLAMINE and PENALDIC ACID.

- Alkaline and the specific enzyme penicillinase are more selective in their action, attacking only the β-
Lactam ring to yield penicilloic acid.

✓ Clinical Uses of the Penicillins:

• Penicillins are given through route or, in more severe infections, intravenously and often in combination
with other antibiotics
• Uses are for sensitive organisms like
- bacterial meningitis (e.g. caused by Neisseria meningitidis, Streptococcus pneumoniae):
benzylpenicillin, high doses intravenously
- bone and joint infections (e.g. with Staphylococcus aureus): flucloxacillin
- skin and soft tissue infections (e.g. with Strep. pyogenes or Staph. aureus): benzylpenicillin,
flucloxacillin; animal bites: co-amoxiclav
- pharyngitis (from Strep. pyogenes): phenoxylmethylpenicillin
- otitis media (organisms commonly include Strep. pyogenes, Haemophilus influenzae): amoxicillin
- bronchitis (mixed infections common): amoxicillin, ampicillin
- pneumonia: amoxicillin, ampicillin
- urinary tract infections (e.g. with Escherichia coli): amoxicillin
- gonorrhea: amoxicillin (plus probenecid )
- syphilis: procaine benzylpenicillin
- endocarditis (e.g. with Strep. viridans or Enterococcus faecalis) & serious infections with
Pseudomonas aeruginosa: ticarcillin, piperacillin.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 3|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

✓ Structure Activity Relationship:

• The strained β-Lactam ring is essential for binding with transpeptidase enzyme.
• The free carboxylic acid is essential.
• The Acylamino side chain is essential (except THIENAMYCIN).

• Sulfur is essential but not essential.

• The stereochemistry of the bicyclic ring with respect to the Acylamino side chain is important.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 4|Page

 BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

The acid sensitivity of penicillins: Why is penicillin G acid sensitive?

There are three reasons for the acid sensitivity of penicillin G.
i. Ring strain.
- The bicyclic system in penicillin consists of a four-membered ring and a five membered ring. As a result,
penicillin suffers large angle and torsional strains.
- Acid-catalysed ring opening relieves these strains by breaking open the more highly strained four-
membered lactam ring

ii. A highly reactive β-lactam carbonyl group.

- The carbonyl group in the β-lactam ring is highly susceptible to nucleophiles and as such does not behave
like a normal tertiary amide which is usually quite resistant to nucleophilic attack. This difference in
reactivity is due mainly to the fact that stabilization of the carbonyl is possible in the tertiary amide, but
impossible in the β-lactam ring.
- The β-lactam nitrogen is unable to feed its lone pair of electrons into the carbonyl group since this would
require the bicyclic rings to adopt an impossibly strained flat system. As a result, the lone pair is localized
on the nitrogen atom and the carbonyl group is far more electrophilic than one would expect for a tertiary
amide. A normal tertiary amide is far less susceptible to nucleophiles since the resonance structures above
reduce the electrophilic character of the carboxyl group.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 5|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

iii. Influence of the acyl side-chain (neighbouring group participation).

The neighbouring acyl group can actively participate in a mechanism to open up the lactam ring. Thus,
penicillin G has a self-destructive mechanism built into its structure.

The tackling problem of acid sensitivity

- It can be seen that countering acid sensitivity is a difficult task. Nothing can be done about the first two
factors since the β-lactam ring is vital for antibacterial activity. Without it, the molecule has no useful
biological activity at all.
- Therefore, only the third factor can be tackled that is if a good electron withdrawing group is attached to
the carbonyl group, then the inductive pulling effect should draw electrons away from the carbonyl
oxygen and reduce its tendency to act as a nucleophile.

- Penicillin V has electronegative oxygen on the acyl side-chain with the electron withdrawing effect
required. The molecule has better acid stability than penicillin G and is stable enough to survive the acid
in the stomach. Thus, it can be given orally.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 6|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

- A range of penicillin analogues which have been very successful are penicillin which is disubstituted on
the alpha-carbon next to the carbonyl group. As long as one of the groups is electron withdrawing, these
compounds are more resistant to acid hydrolysis and can be given orally (e.g. ampicillin and oxacillin).
- So the problem of acid sensitivity is fairly easily solved by having an electron withdrawing group on the
acyl side-chain.

Ampicillin

Penicillin sensitivity to β-lactamases

- β-Lactamases are enzymes produced by penicillin-resistant bacteria which hydrolysis the penicillin.

- The strategy is to block the penicillin from reaching the penicillinase active site. One way of doing that is
to place a bulky group on the side-chain. This bulky group can then act as a 'shield' to ward off the
penicillinase and therefore prevent binding.
- However, there was a problem. If the side-chain was made too bulky, then the steric shield also prevented
the penicillin from attacking the enzyme responsible for bacterial cell wall synthesis.
- Therefore, a great deal of work had to be done to find the ideal 'shield' which would be large enough to
ward off the lactamase enzyme, but would be small enough to allow the penicillin to do its duty.
- The principle of the steric shield can be possible if two ortho-methoxy groups on the aromatic ring. Both
of these are important in shielding the lactam ring.

- However, methicillin is by no means an ideal drug. Since there is no electron withdrawing group on the
side-chain, it is acid sensitive.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 7|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

- So the problem of acid sensitivity by incorporating into the side-chain a five-membered heterocyclic
which was designed to act as a steric shield and also to be electron withdrawing.

- These compounds (oxacillin, cloxacillin, and flucloxacillin) are acid-resistant and penicillinase-resistant,
and are also useful against Staph. aureus infections.
- The only difference between the above three compounds is the type of halogen substitution on the
aromatic ring. The influence of these groups is found to be pharmacodynamic, that is, they influence such
factors as absorption of the drug and plasma protein binding. For example, cloxacillin is better absorbed
through the gut wall than oxacillin, whereas flucloxacillin is less bound to plasma protein, resulting in
higher levels of the free drug in the blood supply.
Narrow spectrum of activity
Penicillins are poor activity against Gram-negative bacteria. There are several reasons for this resistance.
i. Permeability barrier.
- It is difficult for penicillins to invade a Gram-negative bacterial cell due to the make up of the cell wall.
Gram-negative bacteria have a coating on the outside of their cell wall which consists of a mixture of fats,
sugars, and proteins. This coating can act as a barrier in various ways.
- the outer surface may have an overall negative or positive charge depending on its constituent
triglycerides.
- Penicillin has a free carboxylic acid which if ionized would be repelled by the former type of cell
membrane.
- Alternatively, the fatty portion of the coating may act as a barrier to the polar hydrophilic penicillin
molecule.
- The only way in which penicillin can negotiate such a barrier is through protein channels in the outer
coating. Unfortunately, most of these are usually closed
ii. High levels of transpeptidase enzyme produced.
- The transpeptidase enzyme is the enzyme attacked by penicillin. In some gram negative bacteria, a lot of
transpeptidase enzyme is produced, and the penicillin is incapable of inactivating all the enzyme
molecules present.
iii. Modification of the transpeptidase enzyme.
- A mutation may occur which allows the bacterium to produce a transpeptidase enzyme which is not
antagonized by penicillin.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 8|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

iv. Presence of β-lactamase and Transfer of the β-lactamase enzyme.

- Bacteria can transfer small portions of DNA from one cell to another through structures called plasmids.
These are small pieces of circular bacterial DNA. If the transferred DNA contains the code for the (3-
lactamase enzyme, then the recipient cell acquires immunity.

To overcome narrow activity spectrum

- Hydrophobic groups on the side-chain (e.g. penicillin G) favour activity against Gram-positive bacteria,
but result in poor activity against Gram-negative bacteria.
- If the hydrophobic character is increased, there is little effect on the Gram-positive activity, but what
activity there is against Gram-negative bacteria drops even more.
- Hydrophilic groups on the side-chain have either little effect on Gram-positive activity (e.g. penicillin T)
or cause a reduction of activity (e.g. penicillin N). However, they lead to an increase in activity against
Gram-negative bacteria.
- Enhancement of Gram-negative activity is found to be greatest if the hydrophilic group (e.g. NH2, OH,
COOH) is attached to the carbon, alpha to the carbonyl group on the side-chain.
- Those penicillins having useful activity against both Gram-positive and Gram negative bacteria are known
as broad-spectrum antibiotics. There are two classes of broad-spectrum antibiotics. Both have an alpha-
hydrophilic group. However, in one class the hydrophilic group is an amino function as in ampicillin or
amoxycillin.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 9|Page

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

Synergism of penicillin’s with other drugs

- The administration of penicillins with a compound called probenecid.
- Probenecid is a moderately lipophilic carboxylic acid and as such is similar to penicillin.
- It is found that probenecid can block facilitated transport of penicillin through the kidney tubules.
- As a result, penicillin levels in the bloodstream are enhanced and the antibacterial activity increases—a
useful tactic if faced with a particularly resistant bacterium.

BASIC STRUCTURES OF FOUR GROUPS OF Β-LACTAM ANTIBIOTICS AND CLAVULANIC ACID:

- The structures illustrate the β-lactam ring (ring-B) and the sites of action of bacterial enzymes
that inactivate these antibiotics (ring-A → thiazolidine ring).
- Various substituents are added at R1, R2 and R3 to produce agents with different properties.
- In carbapenems, the stereochemical configuration of the part of the β-lactam ring is different
from the corresponding part of the penicillin and cephalosporin molecules; this is probably the
basis of the
β-lactamase resistance of the carbapenems.
- The β-lactam ring of clavulanic acid is thought to bind strongly to β-lactamase, meanwhile
protecting other β-lactams from the enzyme.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 10 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

BACTERIAL CELL WALL OF GRAM-POSITIVE AND GRAM-NEGATIVE STRAINS

- β-Lactams inhibit the synthesis of peptidoglycan which is the major polymer of the bacterial cell wall.
Peptidoglycan maintains the cell shape and protects against osmotic forces. That capability depends on its
netlike structure, composed of long sugar chains crosslinked by peptides.
- In Gram-positive organisms, the peptidoglycan typically forms a thick layer external to the cytoplasmic
membrane and accounts for 50% of the dry weight of the bacterium, whereas in Gram-negative bacteria and
mycobacterium, peptidoglycan is a thinner layer (5), or hydrated gel (6), sandwiched between the outer and
cytoplasmic membranes.
- Gram-positive bacteria are called protoplasts when they lose their cell wall. Gram-negative bacteria do not
lose their cell wall completely and are called spheroplasts after treatment with penicillin.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 11 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

MECHANISM ACTION OF PENICILLIN:

• Normal mechanism by transpeptidase enzyme.

• Penicillin inhibited transpeptidase enzyme.

• An alternative proposition is that penicillin does not bind to the active site itself, but binds instead to a site
nearby. By doing so, the penicillin structure overlaps the active site and prevents access to the normal
reagents-the umbrella effect. If a nucleophilic group (not necessarily in the active site) attacks the β-
lactam ring, the penicillin becomes bound irreversibly, permanently blocking the active site

Alternative 'umbrella' mechanism of inhibition by penicillin.

- All beta-lactam antibiotics contain the same core 4-member "beta-lactam" ring. This ring mimics the shape
of the terminal D-Ala-D-Ala peptide sequence that serves as the substrate for cell wall transpeptidases
that form covalent bonds between different peptidoglycan chains during periods of cell growth. The 4-ring
structure and associated side groups result in tight binding to the active site of transpeptidases (also known
as Penicillin Binding Proteins). Tight binding inhibits enzyme activity, and consequent cell wall formation.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 12 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

PHARMACOKINETIC ASPECTS:
• When given orally, different penicillins are absorbed to differing degrees depending on their stability in
acid and their adsorption to foodstuffs in the gut. Penicillins can be given by intramuscular or intravenous
injection, but intrathecal administration is inadvisable, particularly in the case of benzylpenicillin, as it can
cause convulsions.
• The penicillins are widely distributed in body fluids, passing into joints; into pleural and pericardial
cavities; into bile, saliva and milk; and across the placenta. Being lipid-insoluble, they do not enter
mammalian cells and do not, therefore, cross the blood-brain barrier unless the meninges are inflamed, in
which case they readily reach therapeutically effective concentrations in the CSF as well.
• Elimination of most penicillins occurs rapidly and is mainly renal, 90% being through tubular secretion.
The relatively short plasma half-life is a potential problem in the clinical use of benzylpenicillin.
ADVERSE EFFECTS:
• The major adverse effect is Anaphylactic shock and other Common adverse drug reactions associated
with use of the penicillins include Anaphylaxis (10% patient) diarrhea, hypersensitivity, nausea, rash,
neurotoxicity, urticaria and superinfection (including candidiasis).
• Infrequent adverse effects include fever, vomiting, erythema, dermatitis, angioedema, seizures
(especially in epileptics) and pseudomembranous colitis.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 13 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

ANAPHYLAXIS
- Anaphylaxis is an acute systemic (multi-system) and severe type I hypersensitivity allergic reaction in
humans and other mammals. The term comes from the Greek words ana (against) and phylaxis (protection).
Anaphylactic shock, the most severe type of anaphylaxis, occurs when an allergic response triggers a quick
release of large quantities of immunological mediators (histamines, prostaglandins and leukotrienes) from
mast cells, leading to systemic vasodilatation (associated with a sudden drop in blood pressure) and edema
of bronchial mucosa (resulting in bronchoconstriction and difficulty breathing). Anaphylactic shock can
lead to death in a matter of minutes if left untreated.
- Symptoms of anaphylaxis are related to the action of Immunoglobulin E (IgE) and other anaphylatoxins,
which act to release histamine and other mediator substances from mast cells (degranulation). In addition to
other effects, histamine induces vasodilatation of arterioles and constriction of bronchioles in the lungs, also
known as bronchospasm.
- Symptoms can include: polyuria, respiratory distress, hypotension (low blood pressure), fainting,
unconsciousness, flushed appearance, angioedema (swelling of the lips, face, neck and throat): this can be
life threatening, tears (due to angioedema and stress), vomiting, itching, diarrhea, abdominal pain, anxiety

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 14 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

CLASSIFICATION OF PENICILLINS:
- The first penicillins were the naturally occurring benzylpenicillin and its congeners, including
phenoxymethylpenicillin.
- Benzylpenicillin is active against a wide range of organisms and is the drug of first choice for many
infections. Its main drawbacks are poor absorption in the gastrointestinal tract (which means it must be
given by injection) and its susceptibility to bacterial β-lactamases.
- Various semisynthetic penicillins have been prepared by adding different side-chains to the penicillin
nucleus. In this way, β-lactamase-resistant penicillins (e.g. flucloxacillin) and broad-spectrum penicillins
(e.g. ampicillin , pivampicillin and amoxicillin ) have been produced. Extended-spectrum penicillins
(e.g. ticarcilin) with antipseudomonal activity have also been developed and have gone some way to
overcoming the problem of serious infections caused by P. aeruginosa. Amoxicillin is sometimes
combined with β-lactamase inhibitor clavulanic acid.
There are 4 classes of penicillins, based upon their ability to kill various types of bacteria. From narrow to
broad range of effectiveness they include:
✓ Natural Penicillins (Penicillin G, Procaine-Penicillin G, Penicillin V, Benzathine). The natural penicillins
were the first agents in the penicillin family to be introduced for clinical use. The natural penicillins are
based on the original penicillin-G structure. They are effective against gram-positive strains of
Streptococci, Staphylococci, and some gram-negative bacteria such as Meningococcus. Penicillin V is the
drug of choice for the treatment of Streptococcal pharyngitis. It is also useful for anaerobic coverage in
patients with oral cavity infections.
✓ Penicillinase-Resistant Penicillins (Cloxacillin, Dicloxacillin, Methicillin, Nafcillin, Oxacillin).
Methicillin was the first member of this group, followed by oxacillin, nafcillin, cloxacillin and
dicloxacillin. The penicillinase-resistant penicillins have a more narrow spectrum of activity than the
natural penicillins. Their antimicrobial efficacy is aimed directly against penicillinase-producing strains of
gram-positive cocci, particularly Staphylococcal species and these drugs are sometimes called anti-
staphylococcal penicillins.
✓ Aminopenicillins (Ampicillin, Amoxicillin, Bacampicillin). The aminopenicillins were the first
penicillins discovered to be active against gram-negative bacteria (such as E. coli and H. influenzae).
Aminopenicillins are acid-resistant so administered orally. Orally administered amoxicillin and ampicillin
are used primarily to treat mild infections such as otitis media, sinusitis, bronchitis, urinary tract infections
and bacterial diarrhea. Amoxicillin is the agent of choice for the treatment of otitis media.
✓ Extended Spectrum Penicillins (sometimes called anti-pseudomonal penicillins). Extended Spectrum
Penicillins include both alpha-carboxypenicillins (carbenicillin and ticarcillin) and acylaminopenicillins
(piperacillin, azlocillin and mezlocillin). These agents have similar spectrums of activity as the
aminopenicillins but with additional activity against several gram negative organisms of the family
Enterobacteriaceae, including many strains of Pseudomonas aeruginosa. Like the aminopenicillins, these
agents are susceptible to inactivation by beta-lactamases. These agents may be used alone or in
combination with Aminoglycosides.
Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 15 | P a g e
BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

BENZYL PENICILLIN

It is commonly known as penicillin G. Penicillin G is typically given by a parenteral route of administration

(not orally) because it is unstable in the hydrochloric acid of the stomach. Because the drug is given
parenterally, higher tissue concentrations of penicillin G can be achieved than is possible with
phenoxymethylpenicillin. These higher concentrations translate to increased antibacterial activity.
Specific indications for benzylpenicillin include:
• Cellulitis: It is a diffuse inflammation of connective tissue with severe inflammation of dermal and
subcutaneous layers of the skin. Cellulitis can be caused by normal skin flora or by exogenous bacteria.
• Gonorrhea (also gonorrhoea): It is a common sexually transmitted infection caused by the bacterium
Neisseria gonorrhoeae.
• Meningitis: It is inflammation of the protective membranes covering the brain and spinal cord, known
collectively as the meninges. Some forms of meningitis associated with Meningococci, Haemophilus
influenzae type B, pneumococci or mumps virus infections.
• Aspiration pneumonia, lung abscess.
• Community-acquired pneumonia [Pneumonia is an inflammatory illness of the lung, cause by
Streptococcus pneumoniae].
• Syphilis: It is a sexually transmitted disease caused by the Treponema pallidum. The route of
transmission of syphilis is almost always through sexual contact, although there are examples of
congenital syphilis via transmission from mother to child in utero.
• Septicemia in children
• Septic Arthritis: It is the purulent invasion of a joint by an infectious agent which produces arthritis
Bacteria that are commonly found to cause septic arthritis are Staphylococcus aureus, Haemophilus
influenzae, Haemophilus influenzae, Escherichia coli, Pseudomonas aeruginosa has been found to infect
joints, especially in children who have sustained a puncture wound.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 16 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

PROCAINE BENZYLPENICILLIN

It also known as procaine penicillin, it is a form of penicillin which is a combination of benzylpenicillin and
the local anaesthetic agent procaine. Following deep intramuscular injection, it is slowly absorbed into the
circulation and hydrolysed to benzylpenicillin — thus it is used where prolonged low concentrations of
benzylpenicillin are required.
This combination is aimed at reducing the pain and discomfort associated with a large intramuscular injection
of penicillin. It is widely used in veterinary settings.
Specific indications for procaine penicillin include:
• Syphilis
• Respiratory tract
• Procaine penicillin is also used as an adjunct in the treatment of anthrax [Anthrax is an acute disease
caused by Bacillus anthracis.].
AMPICILLIN
✓ It is a beta-lactam antibiotic that has been used extensively to treat bacterial infections.
✓ Penicillin therapies had only been effective against Gram-positive organisms such as Staphylococci and
Streptococci. Ampicillin also demonstrated activity against Gram-negative organisms such as H.
influenzae, Coli forms and Proteus spp. Ampicillin is closely related to amoxicillin, another type of
penicillin, and both are used to treat urinary tract infections, otitis media, uncomplicated community-
acquired pneumonia, Haemophilus influenzae, Salmonellosis and Listeria meningitis.
AMOXICILLIN
✓ It is formerly known as amoxycillin and it is a moderate-spectrum, bacteriolytic, β-lactam antibiotic used
to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within
the class because it is better absorbed, following oral administration, than other β-lactam antibiotics.
✓ Amoxicillin is susceptible to degradation by β-lactamase-producing bacteria and so may be given with
clavulanic acid to decrease its susceptibility.
✓ Amoxicillin acts by inhibiting the synthesis of bacterial cell wall. It inhibits cross-linkage between the
linear peptidoglycan polymer chains that make up a major component of the cell walls of both Gram-
positive and Gram-negative bacteria.

Ampicillin Amoxicillin
Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 17 | P a g e
BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

CLOXACILLIN

✓ It is a semisynthetic antibiotic in the same class as penicillin.

✓ It is used against staphylococci that produce beta-lactamase, due to its large R chain which doesn't allow
the beta-lactamases to bind.
✓ This drug has a weaker antibacterial activity than benzylpenicillin and is devoid of serious toxicity except
for allergic reactions.
✓ It has been suggested, in one study, that increased use of cloxacillin may permit reduced use of
Vancomycin.
CLAVULANIC ACID
- It was isolated from Streptomyces clavuligerus by Sir Beechams (1976).
- It has weak and unimportant antibiotic activity. However, it is a powerful and irreversible inhibitor of
most
β-lactamases
- It is used in combination with penicillins such as amoxycillin, ampicillin etc.
- It was the first example of a naturally occurring β-lactam ring which was not fused to a sulfur-containing
ring. It is instead fused to an oxazolidine ring structure and it does not have an acylamino side-chain also.
- The essential requirements for β-lactamase activity are:
▪ The β-lactam ring.
▪ Presence of double bond.
▪ The double bond has the Z configuration. (Activity is reduced but not eliminated if the double bond is E.)
▪ No substitution at C6.
▪ (R)-stereochemistry at positions C2 and C5.
▪ The carboxylic acid group.
▪ The variability allowed is therefore strictly limited to the 9-hydroxyl group. Small hydrophilic groups
appear to be ideal, suggesting that the original hydroxyl group is involved in a hydrogen bonding
interaction with the active site of the β-lactamase.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 18 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

❖ β- Lactamase Inhibitors
β-Lactamases are now responsible for resistance to penicillin’s, extended-spectrum cephalosporins,
monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase
inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors
greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in
the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections.

Mechanism of action:
- Clavulanic acid is a mechanism-based irreversible inhibitor and act as a suicide substrate.
- Here Clavulanic acid fits the active site of β-lactamase and the β-lactam ring is opened by a serine
residue in the same manner as penicillin. However, the acyl-enzyme intermediate then reacts further
with another enzymic nucleophilic group (possibly NH2) to bind the drug irreversibly to the enzyme.
The mechanism requires the loss or gain of protons at various stages and an amino acid such as
histidine present in the active site would be capable of acting as a proton donor/acceptor.
Clavulanic acid as an irreversible mechanism based inhibitor and
act as a suicide substrate over the active site of β-lactamase enzyme.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 19 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

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BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

❖ Cephalosporin
✓ The cephalosporins, was isolated from fungus Cephalosporium acremonium by Sir Brotzu in 1948,
obtained from sewer waters on the island of Sardinia.
✓ The structure of cephalosporin C has similarities to that of penicillin in that it has a bicyclic system
containing a four-membered β-lactam ring. However, the β-lactam ring is fused with a six-membered
dihydrothiazine ring, which have larger ring relieves strain in the bicyclic system to some extent, but it is
still a reactive system.
✓ Biosynthetic precursors of cephalosporin are cysteine and valine.

✓ Cephalosporin C, the component of special interest , is not potent enough to be a useful antibiotic, but
removal , through chemical means, of the natural side chain produced 7-aminocephalosporanic acid (7-
ACA), which, analogous to 6-APA, could be fitted with unnatural side chains.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 21 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

METABOLISM
▪ Those cephalosporins that have an acetyl group in the side chain are subject to enzymatic hydrolysis in the
body. The result is molecules with a hydroxymethyl moiety at C-3. A hydroxy moiety is a poor leaving
group, so this change is considerably deactivating with respect to breakage of the β-lactam bond.
▪ In addition, the particular geometry of this part of the molecule leads to facile lactonization with the
carboxyl group attached to C-2
▪ Lactonization masks this docking functional group and, as a result, blocks affinity of the inhibitor for the
enzyme.

Metabolism of C-3-acetyl–substituted cephalosporins

ALLERGENICITY
Allergenicity is less commonly experienced and is less severe with cephalosporins than with penicillins.
Cephalosporins frequently are administered to patients who have had a mi ld or delayed penicillin reaction.
Cross-allergenicity is comparatively common, however, and cephalosporins should be administered with
caution for patients who have a history of allergies. Patients who have had a rapid and severe reaction to
penicillins should not be treated with cephalosporins.
THERAPEUTIC USES
▪ The cephalosporins are used widely and are therapeutically important antibiotics.
▪ Clinical studies have shown cephalosporins to be effective as both therapeutic and prophylactic agents.
▪ The first-generation cephalosporins are excellent agents for skin and soft tissue infections owing to S.
aureus and S. pyogenes. A single dose of cefazolin just before surgery is the preferred prophylaxis for
procedures in which skin flora are the likely pathogens
▪ For colorectal surgery, where prophylaxis for intestinal anaerobes is desired, the second-generation agents
cefoxitin or cefotetan are preferred.
▪ The oral second-generation cephalosporins can be used to treat respiratory tract infections, for treatment
of penicillin-resistant S. pneumoniae pneumonia and otitis media.
▪ The third-generation cephalosporins, with or without aminoglycosides, have been considered to be the
drugs of choice for serious infections caused by Klebsiella, Enterobacter, Proteus, Providencia, Serratia,
and Haemophilus spp.
▪ Ceftriaxone is the therapy of choice for all forms of gonorrhea and for severe forms of Lyme disease.
▪ The third-generation cephalosporins cefotaxime or ceftriaxone are used for the initial treatment of
meningitis in nonimmunocompromised adults and children.
▪ They are also used for the treatment of meningitis caused by H. influenzae, sensitive S. pneumoniae, N.
meningitidis, and gram-negative enteric bacteria.
▪ The fourth-generation cephalosporins are indicated for the empirical treatment of nosocomial infections
where antibiotic resistances owing to extended-spectrum β-lactamases or chromosomally induced β-

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BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

lactamases are anticipated. For example, cefepime has superior activity against nosocomial isolates of
Enterobacter, Citrobacter, and Serratia spp. compared with ceftazidime and piperacillin.

ADVERSE EFFECTS
Aside from mild or severe allergic reaction, the most commonly experienced cephalosporin toxicities are mild
and temporary nausea, vomiting, and diarrhea associated with disturbance of the normal flora. Rarely, a life-
threatening pseudomembranous colitis diarrhea associated with the opportunistic and toxin-producing
anaerobic pathogen, Clostridium difficile, can be experienced. Rare blood dyscrasias, which can even include
aplastic anemia, also are seen.
STRUCTURE-ACTIVITY RELATIONSHIP

▪ Various molecular changes in the cephalosporin can improve in vitro stability, antibacterial activity, and
stability toward β-lactamases.
▪ The addition of an amino and a hydrogen to the α and α′ position, respectively, results in a basic
compound that is protonated under the acidic conditions of the stomach. The ammonium ion improves the
stability of the β-lactam of the cephalosporin, leading to orally active drugs.
▪ The 7β amino group is essential for antimicrobial activity (X = H), whereas replacement of the hydrogen
at C-7 (X = H) with an alkoxy (X = OR) results in improvement of the antibacterial activity of the
cephalosporin. Within specific cephalosporin derivatives, the addition of a 7α methoxy also improves the
drugs stability toward β-lactamase.
▪ The derivatives where Y = S exhibit greater antibacterial activity than if Y = O, but the reverse is true
when stability toward β-lactamase is considered.
▪ The 6α hydrogen is essential for biological activity.
▪ The stability of cephalosporins toward β-lactamase, depends on
- The L-isomer of an α amino α′ hydrogen derivative of a cephalosporin was 30- to 40- fold more stable
than the D-isomer.
- The addition of a methoxyoxime to the α and α′ positions increased stability nearly 100-fold.
- The Z-oxime was as much as 20,000-fold more stable than the E-oxime.

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 23 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

DEGRADATION OF CEPHALOSPORINS: Cephalosporins experience a variety of hydrolytic degradation

reactions.

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BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

Classification of cephalosporin analogues.

FIRST GENERATION
………………………………………………………………………………………………………………………………………………………………..

Name R1 R2

Cefazoline

……………………………………………………………………………………………………………………...................................................................

Cephalexin

……………………………………………………………………………………………………………………………………………………………….

Cefadroxil

SECOND GENERATION
……………………………………………………………………………………………………………………………………………………………….

Name R1 R2

Cefaclor

………………………………………………………………………………………………………………

Cefoxitin

………………………………………………………………………………………………………………

Cefprozil

………………………………………………………………………………………………………………

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BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

THIRD GENERATION
………………………………………………………………………………………………………………………………………………………………...

Name R1 R2

Cefotaxime

…………………………………............................................................................................................................................................................................

Cefpodoxime

………………………………………………………………………………………………………………………………………………………………

Ceftizoxime -H
Hydrogen

……………………………………………………………………………………………………………………………………………………………….

Cefdinir

………………………………………………………………………………………………………………………………………………………………

FOTH GENERATION
………………………………………………………………………………………………………………………………………………………………

Name R1 R2

Cefepime

………………………………………………………………………………………………………………………………………………………………

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 26 | P a g e

BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

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 BP 601T: MEDICINAL CHEMISTRY – III UNIT- I: Antibiotics: β-lactam antibiotics

❖ Monobactams
- Monobactams are monocyclic and bacterially produced β-lactam antibiotics.
- Monobactams are effective only against aerobic Gram-negative bacteria (e.g., Neisseria, Pseudomonas).
- Adverse effects to monobactams can include skin rash and occasional abnormal liver functions.
- Monobactam antibiotics exhibit no IgE cross-reactivity reactions with penicillin but have shown some
cross reactivity with cephalosporins, most notably ceftazidime, which contains an identical side chain as
aztreonam. Monobactams can trigger seizures in patients with history of seizures, although the risk is lower
than with penicillin.
- Examples of monobactams are Aztreonam, Tigemonam, Nocardicin A, and Tabtoxin.
- Monobactams are basically such type of antibiotics in which the following features are found.
• It is monocyclic and contains β-lactam ring.
• Here the β-lactam ring is not fused to the adjacent ring, just like most of other β-lactams.
• It generally contains a -SO3H group.
• They are only effective against aerobic gram-negative bacteria.

- Chemistry of Monobactams
• As the monobactam nucleus exhibits weak antibacterial activity, molecular substitution around the
central nucleus is essential to understand the antibacterial potential of these molecules.
• When the side chain substitution of the monobactam nucleus, then it shows primarily Gram-positive,
primarily Gram-negative or broad-spectrum activity.
• The most prominent gain in anti-bacterial activity is observed when an amino-thiazole-oxime side
chain as the 3-acyl substituent is introduced.
• Substitution at the 4-position of the monocyclic ring although capable of producing dramatic changes
in biological activity which is highly unpredictable.
• In the SO3-activated molecules 4-substitution is essential for beta-lactamase stability.
• The 'activating' group on the beta-lactam nitrogen is responsible for the activation of the beta-lactam
ring and it can be varied quite widely while retaining high intrinsic activity.

“God is not present in idols. Your feelings are your god. The soul is your temple.”

Dr. S. Mondal_Lecturer Notes_ B. Pharm 4th Semester_GITAM (Deemed to be University) 28 | P a g e

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