Penicillin Classification, Mechanism of Action, Structure Activity Relationship, Structure of Penicillins, penicillin-binding proteins (PBPs) functional propertiesCross-linking of the peptidoglycan by transpeptidases, Cross-linking of the peptidoglycan by transpeptidases, Shape of penicillin G Penicillin SAR AcylSide Chain Modifications Instability of β-lactams to nucleophiles
Penicillinase-Resistant Penicillins Protein Binding of Penicillins
2. INTRODUCTION
• Antibiosis-process by which one organism destroys
another to preserve itself by producing a metabolite &
the metabolic substance is Antibiotic
• Definition : A substance produced by microorganisms,
which has capacity of inhibiting the growth or
destroying other microorganisms at low
concentrations without affecting host to a
considerable extent.
3. INTRODUCTION
A substance is classified as an antibiotic if
• It is a product of metabolism (although it may be duplicated or
even have been anticipated by chemical synthesis).
• It is a synthetic product produced as a structural analog of a
naturally occurring antibiotic.
• It antagonizes the growth or survival of one or more species of
microorganisms.
• It is effective in low concentrations.
4. HISTORY OF ANTIBIOTICS
• 500-600 BC molded curd of soyabean used to treat boils &
carbuncles in Chinese folk medicine.
• Moldy Cheese to treat wounds in Ukraine
• 1877- Pasteur & Jobuert – anthrax bacilli killed in presence of
certain bacteria
• 1889 – Vuilemin coined termed antibiosis (against life)
• 1929 – Alexander Fleming accidental discovery of antibacterial
effects of penicillium.
• 1938- florey & Chain brought Penicillin in Clinical practice
• Waksman proposed defination of anitbiotics
5. CURRENT STATUS OF ANTIBIOTICS
• Commercial and scientific interest
• Thousands isolated& identified antibiotic substances
• Numerous semisynthetic and synthetic derivatives
8. SELECTING A METABOLITE AS A
ANTIBIOTIC
In addition to the ability to combat infections or neoplastic disease, the
antibiotic must possess
• First, selective toxicity to be effective against pathogenic microorganisms/
neoplastic tissue, without causing significant toxic effects.
• Second, chemically stable when isolated, processed, and stored for a reasonable
length of time without deterioration of potency & then convereted to suitable
dosage forms to provide active drug in vivo.
• Third, biotransformation and elimination should be slow enough to allow a
convenient dosing schedule, yet rapid and complete enough to facilitate removal
of the drug and its metabolites from the body soon after administration has
been discontinued.
• Some groups of antibiotics, because of certain unique properties, have been
designated for specialized uses, such as the treatment of tuberculosis(TB) or
fungal infections or anticancer.
• Also used in animal and plant disease too..
9. MECHANISMS OF ANTIBIOTIC
ACTION
Site of
action
Antibiotic Process interrupted Type of
Activity
Cell wall Bacitracin Mucopeptide synthesis Bactericidal
Cephalosporin Cell wall cross-linking Bactericidal
Cycloserine Synthesis of cell wall
peptides
Bactericidal
Penicillins Cell wall cross-linking Bactericidal
Vancomycin Mucopeptide synthesis Bactericidal
Cell
membrane
Amphotericin
B
Membrane function Fungicidal
Nystatin Membrane function Fungicidal
10. MECHANISMS OF ANTIBIOTIC
ACTION
Site of
action
Antibiotic Process interrupted Type of
Activity
Ribosomes
50S subunit
Chloramphenic
ol
Protein synthesis Bacteriostatic
Erythromycin Protein synthesis Bacteriostatic
Lincomycins Protein synthesis Bacteriostatic
30S subunit Aminoglycosid
es
Protein synthesis and fidelity Bactericidal
Tetracyclines Protein synthesis Bacteriostatic
Nucleic
acids
Actinomycin DNA and mRNA synthesis Pancidal
Griseofulvin Cell division, microtubule
assembly
Fungistatic
11. ΒETA-LACTAMS
• Possess β-lactam (4-membered cyclic amide) ring
structure are the dominant class of agents
• Used for the chemotherapy of bacterial infections.
• The 1st antibiotic to be used in therapy, penicillin
(penicillin G),
• Phenoxymethyl penicillin (penicillin V) biosynthetic are
first choice for the treatment of infections caused by most
species of Gram-positive bacteria.
• Penicillins & cephalosporins are resistant to penicillinase-
producing staphylococci and Gram-negative bacilli.
12. PENICILLIN CLASS DRUGS
• Ampicillin
• Amoxacillin
• Bacampicillin
• Benzylpenicillin
• Carbenicillin and indanyl
carbenicillin
• Clavulanic acid
• Methicillin
• Mezlocillin and piperacillin
• Nafcillin
• Oxacillin, cloxacillin, and
dicloxacillin
• Phenoxymethyl penicillin
• Piperacillin and tazobactam
• Sulbactam
• Ticarcillin
16. BETA-LACTAM
• A beta-lactam (β-lactam) ring is a four-membered
lactam.
• A lactam is a cyclic amide, and beta-lactams are
named so because the nitrogen atom is attached to
the β-carbon atom relative to the carbonyl.
• The simplest β-lactam possible is 2-azetidinone.
19. NUMBERING
SYSTEMS
Two numbering systems for the
fused bicyclic heterocyclic
system exist.
The Chemical Abstracts system
initiates the numbering with the
sulfur atom and assigns the ring
nitrogen the 4-position.
4-thia-l-
azabicyclo[3.2.0]heptanes,
The numbering system adopted
by the USP is the reverse of the
Chemical Abstracts procedure,
assigning number 1 to the
nitrogen atom & number 4 to the
26. MECHANISM OF ACTION
• Two properties contribute to the unequaled importance of β-lactam
antibiotics in chemotherapy:
1. Potent and rapid bactericidal action against bacteria in the growth phase and
2. Very low frequency of toxic and other adverse reactions in the host.
• The uniquely lethal antibacterial action of these agents has been
attributed to a selective inhibition of bacterial cell wall synthesis.
• Specifically, the basic mechanism involved is inhibition of the
biosynthesis of the dipeptidoglycan that provides strength and rigidity
to the cell wall.
27. MECHANISM OF ACTION
• Penicillins and cephalosporins acylate a specific bacterial D-
transpeptidase, thereby rendering it inactive for its role in forming
peptide cross-links of two linear peptidoglycan strands by
transpeptidation and loss of D-alanine.
• Bacterial D-alanine carboxypeptidases are also inhibited by beta-
lactam antibiotics.
28. MECHANISM OF ACTION
• Penicillins and cephalosporins acylate a specific bacterial D-transpeptidase,
thereby rendering it inactive for its role in forming peptide cross-links of two
linear peptidoglycan strands by transpeptidation and loss of D-alanine.
• Bacterial D-alanine carboxypeptidases are also inhibited by Beta-lactam
antibiotics.
• Binding studies with tritiated benzylpenicillin have shown that the
mechanisms of action of various beta–lactam antibiotics are much more
complex than previously assumed.
• Studies in E. coli have revealed as many as seven different functional proteins,
each with an important role incell wall biosynthesis.
29. PENICILLIN-BINDING PROTEINS (PBPS)
FUNCTIONAL PROPERTIES
• PBPs 1a and 1b are transpeptidases involved in peptidoglycan synthesis
associated with cell elongation.
• Inhibition results in spheroplast formation and rapid cell lysis, caused by
autolysins (bacterial enzymes that create nicks in the cell wall for
attachment of new peptidoglycan units or for separation of daughter cells
during cell division10).
• PBP 2 is a transpeptidase involved in maintaining the rod shape of bacilli.
• Inhibition results in ovoid or round forms that undergo delayed lysis.
• PBP 3 is a transpeptidase required for septum formation during cell
division.
• Inhibition results in the formation of filamentous forms containing rod-
shaped units that cannot separate. It is not yet clear whether inhibition of
PBP 3 is lethal to the bacterium.
30. PENICILLIN-BINDING PROTEINS (PBPS)
FUNCTIONAL PROPERTIES
• PBPs 4 through 6 are carboxypeptidases responsible for the hydrolysis of
D-alanine–D-alanine terminal peptide bonds of the cross-linking peptides.
• Inhibition of these enzymes is apparently not lethal to the bacterium,13
even though cleavage of the terminal D-alanine bond is required before
peptide cross-linkage.
• The various Beta-lactam antibiotics differ in their affinities for PBPs.
• Penicillin G binds preferentially to PBP 3, whereas
• the first-generation cephalosporins bind with higher affinity to PBP 1a.
• In contrast to other penicillins and to cephalosporins, which can bind to
PBPs 1, 2, and 3, amdinocillin binds only to PBP 2
37. PENICILLIN SAR
No Substitution
allowed
Sulphur is
required but not
mandatory
Thiazolidine ring,
essential for
activity
Carboxylic Acid:
Involved in ionic
interactions with N of lysine
at binding site
Activity ↓ if reduced by -
COOR or -CHOH
Trans -
stereochemistry is
required with COOH
Acylamino sidechain:
EWG make amide less
Nucleophilic,
Bulky gr provides steric
hindrance to β-lactamase
Polar grs make it more
hydrophobic
Carbonyl Group:
Lone pair e- of N do not
resonate to carbonyl
group hence is venerable
to nucleophilic attack
Bicyclic system :
Puts a strain on the β-lactam ring
Strain directly proportional to instability
of the structure
β-lactam
strained ring
Dimethyl group:
Essential, removal
↓activity
39. SAR
• 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. It is replaceable as in case with Carbapenems
• Position 2 – No substitutions allow at this position, any change will lower
activity. The methyl groups are necessary
• Position 3 – The carboxylic acid of the Thiazolidine is required for activity. It
ionizes & the has ionic interactions with a lysine moiety at receptor site increase
the affinity towards the macromolecule. If it is changed to an alcohol or ester,
activity is decreased.
• Position 4 – The nitrogen is a must.
• Position 5 – No substitutions allowed.
40. SAR
• Position 7 – The carbonyl on the Beta-lactam ring is a must.
• Position 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.
• A bulky group added close to the ring will make the
compound more resistant to Beta-lactamases.
• Steric hindrance provides protect to the Beta-lactam ring.
41. Β-LACTAM RING OPENING BY
ACYLAMINO SIDE-CHAIN
• the acylamino side-chain can help aid the ring-opening of the β-
lactam ring.
• It can act as an internal nucleophile and attack the β-lactam carbonyl
forming a very strained intermediate that then opens to break the β-
lactam ring.
• This makes the penicillin inactive and is sometimes described as a
‘self-destruct’ mechanism.
42. MODIFICATION OF ACYLAMINO SIDE-
CHAIN
• Placing an electron-withdrawing substituent(EWS) within the side-
chain reduces nucleophilicity of acyl carbonyl
• The EWS group accepts electrons & makes the amide carbonyl
group a weaker nucleophile, which is less likely to react with the β-
lactam carbonyl.
• For example, penicillin G is more prone to ‘self-destruct’ than
penicillin V, or phenoxymethylpenicillin.
43. PENICILLIN STEREOCHEMISTRY
• C5 & C6 –H should have cis orientation.
• C6 –NH2 & C2 –COOH should have trans orientation.
• Change in orientation increases instability & hence reduces activity.
48. Β-LACTAMASE RESISTANT/SENSITIVE
STRUCTURAL FEATURES
• When the aromatic ring is attached directly to the side chain carbonyl and
both ortho-positions are substituted by methoxy groups,b-lactamase stability
results
• Movement of one of the methoxy groups to the para position or replacing one
of them with a hydrogen results in an analog sensitive to beta-lactamases.
• Putting in a methylene between the aromatic ring and 6-APA likewise
produces a b-lactamase–sensitive agent
49. Β-LACTAMASE RESISTANT/SENSITIVE
STRUCTURAL FEATURES
• Stability of the penicillins toward β-lactamase is influenced by the
bulk in the acyl group attached to the primary amine.
• β-Lactamases are much less tolerant to the presence of steric
hindrance near the side-chain amide bond than are the penicillin
binding proteins(PBPs).
• When the aromatic ring is attached directly to the side-chain
carbonyl and both ortho-positions are substituted by methoxy
groups, β-lactamase stability results
50. BETA-LACTAMASE
RESISTANT/SENSITIVE STRUCTURAL
FEATURES
• Movement of one of the methoxy groups to the para-position, or
replacing one of them by a hydrogen, resulted in an analogue sensitive
to β-lactamases.
• Putting in a methylene between the aromatic ring and 6-APA likewise
produced a β-lactamase–sensitive agent.
• These findings provide strong support for the hypothesis that its
resistance to enzyme degradation is based on differential steric
hindrance.
• Prime examples of this effect are seen in the drugs methicillin, nafcillin,
54. METHICILLIN
• Methicillin is the first of the penicillinase-resistant agents to reach the
clinic.
• It is unstable to gastric acid, having a half- life of 5 minutes at pH 2, so it has
to be administer via injection.
• Increased bulk resulting from the addition of the dimethoxybenzoyl group
to 6-APA leads to methicillin being a b-lactamase–resistant drug.
• Methicillin has significantly narrower antimicrobial spectrum and less
potency.
55. METHICILLIN
• Substitutions at the ortho positions of a phenylring increase the steric
hindrance of the acyl group and confer more beta-lactamase resistance than
shown by the unsubstituted compounds or those substituted at positions more
distant from the alpha-carbon.
• Bulkier substituents are required to confer effective beta-lactamase resistance
among five-membered–ring heterocyclic derivatives
• Clinical use primarily for parenteral use in infections due to b-lactamase
producing S. aureus and a few other infections.
• An increasing number of infections are caused by MRSA.
• In these organisms, an altered PBP is formed that has a very low affi nity for
beta-lactams, excluding ceftaroline.
• Furthermore, methicillin is an efficient inducer of penicillinases.
• Consequently this drug fell out of favor, and methicillin has now been replaced.
56. NAFCILLIN
• Nafcillin has a 2-ethoxynaphthylside chain.
• This bulky group serves to inhibit destruction by b-
lactamases analogous to methicillin.
• Although slightly more acid stable than methicillin, it is
clinically virtually identical to it.
57. OXACILLIN & DICLOXACILLIN
• Using a substituted isoxazolyl ring as a bioisosteric replacement for
the benzene ring of penicillin G produces the isoxazolyl penicillins.
• Chemically, they differ from one another by chlorine substituents on
the benzene ring.
• Like methicillin, these are generally less potent than
benzylpenicillin against gram-positive microorganisms (generally
staphylococci and streptococci) that do not produce a b-lactamase
but retain their potency against those that do.
• They are more acid stable; thus they may be taken orally, and they
are more potent as well.
58. OXACILLIN & DICLOXACILLIN
• Because they are highly serum protein bound, they are not good
choices for treatment of septicemia.
• Microorganisms resistant against methicillin are also resistant to the
isoxazolyl group of penicillins.
• Like nafcillin, the isoxazolyl group of penicillins is primarily used
against penicillinase-producing Staphylococcus aureus
60. AMPICILLIN
• One of the hydrogen atoms of the side chain methylene has been replaced
with a primary amino group to produce an R-phenylglycine moiety .
• Significant acid stability - oral use.
• Gram-negative pathogens are sensitive to ampicillin.
• Greater penetration of ampicillin into gram negative bacteria.
• The acid stability is due to electron-withdrawing character of the
protonated primary amine group reducing participation in hydrolysis of the
b-lactam bond as well as to the comparative difficulty of bringing another
positively charged species (H3O+) into the vicinity of the protonated amino
group.
• The oral activity is also enhanced, in part, to active uptake by the dipeptide
transporters.
• It unfortunately lacks stability toward b-lactamases, and resistance is
increasingly common.
61. BACAMPICILLIN
• Prodrug
• It is a weak base and is very well absorbed in the duodenum.
• Enzymatic ester hydrolysis in the gut wall liberates carbon
dioxide and ethanol followed by spontaneous loss of
acetaldehyde and production of ampicillin.
• The acetaldehyde is metabolized oxidatively by alcohol
dehydrogenase to produce acetic acid, which joins the normal
metabolic pool.
• Amoxicillin, which has better oral availability than ampicillin has
made the reduced use of bacampicillin.
62. AMOXICILLIN
• Close analog of ampicillin
• para-phenolic hydroxyl group in the side-chain phenyl moiety.
• The isoelectric point of the drug to a more acidic value and has enhanced
blood levels as compared with ampicillin.
• Better oral absorption leads to less disturbance of the normal GI flora and,
therefore, less drug-induced diarrhea.
• The antimicrobial spectrum similar to ampicillin.
• Coadministered with clavulanic acid combination (Augmentin) in which the
clavulanic acid serves to protect amoxicillin to a considerable extent against
b-lactamases.
• This expands the spectrum of activity to include organisms and strains that
produce b-lactamases.
63. CARBENICILLIN
• Semisynthetic Penicillin (1970),
• It has an ionizable carboxyl group substituted on the alpha-
carbon atom of the benzyl side chain.
• Broad range of antimicrobial activity b’coz of the unique
carboxyl group.
• The carboxyl group improves penetration of the molecule
through cell wall barriers of Gram-negative bacilli, compared
with other penicillins.
• Carbenicillin is not stable in acids and is inactivated by
penicillinase.
• It is a malonic acid derivative and decarboxylates readily to
penicillin G, which is acid labile.
64. CARBENICILLIN
• Effective in the treatment of systemic & UTI caused by P.
aeruginosa, indole-producing Proteus spp., and Providencia
spp., all of which are resistant to ampicillin.
• The low toxicity permits the use of large dosages in serious
infections.
• A combination of carbenicillin and gentamicin is for serious
pseudomonal and mixed coliform infections. The two
antibiotics are chemically incompatible, however, and
should never be combined in an intravenous solution.
65. TICARCILLIN
• Ticarcillin disodium, 2-carboxy-3-thienylpenicillin (Ticar), is an
isostere of carbenicillin in which the phenyl group is replaced by a
thienyl group.
• This semisynthetic penicillin derivative, unstable in acid,
administered parenterally.
• It is similar to carbenicillin in antibacterial spectrum &
pharmacokinetic properties.
• Two advantages for ticarcillin are clamied:
(a) slightly better pharmacokinetic properties, including higher serum
levels and a longer duration of action; and
(b) greater in vitro potency against several species of Gramnegative
bacilli, most notably P. aeruginosa and Bacteroides fragilis.
• These advantages can be crucial in the treatment of serious
infections requiring high-dose therapy.
66. MEZLOCILLIN
• Acylureidopenicillin spectrum similar to
that of carbenicillin and ticarcillin;
however, there are some major
differences.
• It is much more active against most
Klebsiella spp., P. aeruginosa,
anaerobic bacteria (e.g., Streptococcus
faecalis and B. fragilis), and H.
influenzae.
• It is recommended for the treatment of
serious infections caused by these
organisms.
67. PIPERACILLIN
• Most useful of the extended-spectrum acylureidopenicillins.
• It is more active than mezlocillin against susceptible strains of Gram-
negative aerobic bacilli, such as Serratia marcescens, Proteus,
Enterobacter, Citrobacter spp., and P. aeruginosa.
• Mezlocillin, however, appears to be more active against Providencia spp.
and K. pneumoniae.
• Piperacillin is also active against anaerobic bacteria, especially B. fragilis
and S. faecalis (enterococcus).
• Beta-Lactamase–producing strains of these organisms are, however,
resistant to piperacillin, which is hydrolyzed by S. aureus beta-lactamase.
• The Beta- lactamase susceptibility of piperacillin is not absolute because
Beta- lactamase–producing, ampicillin-resistant strains of N. gonorrhoeae
and H. influenzae are susceptible to piperacillin.
The nomenclature of penicillins is somewhat complex and
very cumbersome. Two numbering systems for the fused bicyclic
heterocyclic system exist. The Chemical Abstracts
system initiates the numbering with the sulfur atom and assigns
the ring nitrogen the 4-position. Thus, penicillins are
named as 4-thia-l-azabicyclo[3.2.0]heptanes, according to
this system. The numbering system adopted by the USP is
the reverse of the Chemical Abstracts procedure, assigningnumber 1 to the nitrogen atom and number 4 to the sulfur
atom. Three simplified forms of penicillin nomenclature
have been adopted for general use. The first uses the name
“penam” for the unsubstituted bicyclic system, including the
amide carbonyl group, with one of the foregoing numbering
systems as just described. Thus, penicillins generally are
designated according to the Chemical Abstracts system as 5-
acylamino-2,2-dimethylpenam-3-carboxylic acids. The second,
seen more frequently in the medical literature, uses the
name “penicillanic acid” to describe the ring system with
substituents that are generally present (i.e., 2,2-dimethyl and
3-carboxyl). A third form, followed in this chapter, uses trivial
nomenclature to name the entire 6-carbonylaminopenicillanic
acid portion of the molecule penicillin and thendistinguishes compounds on the basis of the R group of the
acyl portion of the molecule. Thus, penicillin G is named
benzylpenicillin, penicillin V is phenoxymethylpenicillin,
methicillin is 2,6-dimethoxyphenylpenicillin, and so on. For
the most part, the latter two systems serve well for naming
and comparing closely similar penicillin structures, but they
are too restrictive to be applied to compounds with unusual
substituents or to ring-modified derivative
Penicillin acts by inhibiting the transpeptidase enzyme - it mimics a peptidoglycan chain and an ester is formed that joins the penicillin to the enzyme. As the penicillin group is so large, it prevents attack of a nucleophile at the ester carbonyl and so the ester does not react with the second peptidoglycan chain. With the enzyme unable to form cross-links the peptidoglycan wall begins to degrade. No new peptidoglycan chains can be added to the cell wall and eventually the cell bursts.
the basic structure of penicillin consists of a β-lactam ring and an acylamino side chain (RCONH–). Based on the mode of action, the β-lactam ring is clearly crucial for its biological activity – the carbon atom in the C=O of the lactam is particularly electrophilic (δ+) and the adjacent thiazolidine ring confers further strain on the β-lactam ring, making it even more reactive to nucleophilic attack. The carboxylic acid group is also important – this is normally deprotonated within the body and the negatively charged carboxylate ion (RCO2–) binds to a positively charged amino acid within the active site of the transpeptidase enzyme.
At the top of the β-lactam ring, a cis–arrangement of hydrogens (both on the same side of the ring) is required for the biological activity, as is an acylamino side chain at the ‘top left’.
This acts as an electron-withdrawing group (the nitrogen atom accepts electron density from the β-lactam carbonyl making it an even stronger electrophile).
Of the three C=O bonds in the penicillin, the β-lactam carbonyl is the most electrophilic. The C=O bond in the acylamino side-chain is not susceptible to nucleophilic attack, because, as is typical of amides, the nitrogen atom can feed its lone pair into the carbonyl group which makes it a weaker electrophile.
Similarly, the C=O bond in the carboxylic acid side-chain, or the carboxylate ion, is not susceptible to nucleophilic attack because the oxygen atom can feed its lone pair into the adjacent carbonyl group. (The wavy lines indicate only a partial structure is shown.)
At the top of the β-lactam ring, a cis–arrangement of hydrogens (both on the same side of the ring) is required for the biological activity, as is an acylamino side chain at the ‘top left’.
This acts as an electron-withdrawing group (the nitrogen atom accepts electron density from the β-lactam carbonyl making it an even stronger electrophile).
Of the three C=O bonds in the penicillin, the β-lactam carbonyl is the most electrophilic. The C=O bond in the acylamino side-chain is not susceptible to nucleophilic attack, because, as is typical of amides, the nitrogen atom can feed its lone pair into the carbonyl group which makes it a weaker electrophile.
Similarly, the C=O bond in the carboxylic acid side-chain, or the carboxylate ion, is not susceptible to nucleophilic attack because the oxygen atom can feed its lone pair into the adjacent carbonyl group. (The wavy lines indicate only a partial structure is shown.)
Penicillin V contains an electronegative oxygen in the PhO substituent, which draws the electron density away from the amide carbonyl group and so reduces its tendency to act as a nucleophile and react with the β-lactam ring. This has important consequences. While penicillin V is stable enough to survive the acidic aqueous conditions in the stomach and so can be taken as a tablet (which is typically preferred by patients), penicillin G does not and so needs to be administered by an injection.
At the top of the β-lactam ring, a cis–arrangement of hydrogens (both on the same side of the ring) is required for the biological activity, as is an acylamino side chain at the ‘top left’.
This acts as an electron-withdrawing group (the nitrogen atom accepts electron density from the β-lactam carbonyl making it an even stronger electrophile).
Of the three C=O bonds in the penicillin, the β-lactam carbonyl is the most electrophilic. The C=O bond in the acylamino side-chain is not susceptible to nucleophilic attack, because, as is typical of amides, the nitrogen atom can feed its lone pair into the carbonyl group which makes it a weaker electrophile.
Similarly, the C=O bond in the carboxylic acid side-chain, or the carboxylate ion, is not susceptible to nucleophilic attack because the oxygen atom can feed its lone pair into the adjacent carbonyl group. (The wavy lines indicate only a partial structure is shown.)
the basic structure of penicillin consists of a β-lactam ring and an acylamino side chain (RCONH–). Based on the mode of action, the β-lactam ring is clearly crucial for its biological activity – the carbon atom in the C=O of the lactam is particularly electrophilic (δ+) and the adjacent thiazolidine ring confers further strain on the β-lactam ring, making it even more reactive to nucleophilic attack
The substitution of a side-chain R group on the primary amine with an electron-withdrawing group decreases
the electron density on the side-chain carbonyl and protects these penicillins, in part , from acid degradation.
This property has clinical implications, because these compounds survive passage through the stomach
better and many can be given orally for systemic purposes. The survival of passage and degree of
absorption under fasting conditions is shown in Table
In addi tion, in vi tro degradat ion reactions of penici ll ins can be retarded by keeping the pH of solut ions
between 6.0 and 6.8 and by refrigerating them. Metal ions, such as mercury, zinc, and copper, catalyze the
degradat ion of penicil l ins, so they should be kept from contact wi th penici ll in solutions. The lids of
containers used today are routinely made of inert plast ics, in par t, to minimize such problems.