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262 Chemistry and Biology of Beta-Lactams
R
1
R
2
R
1
R
2
i) Al
R
3
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created a suitable intermediate, through C–N bond cleavage. The unstable intermediate then suffered the
C–C bond ssion to form the unsaturated compound (Scheme 8.52).
8.3.6 Use of β-Lactams as Scaffold
The diverse scaffolding role of β-lactams is presented here (Scheme 8.53). This is possible for all the
possible reactive sites around the ring.
8.3.7 β-Lactam as a Molecular Lock
Like many other activities, β-lactam can serve as a molecular lock.46 A β-lactam-fused bis-propargylic
sulfone was synthesized successfully by an oxidation reaction, and this failed to isomerize to the stable
allenic sulfone. Similar propargyl to allene derivative isomerization was possible in some compounds
proving the role of β-lactam as a molecular lock. An opening of β-lactam ring to form an allene compound and subsequent DNA damage were targeted (Scheme 8.54).
Ban et al.47 reported the synthesis of fused enediyne β-lactam. The ability of the ring to act as a
molecular lock was demonstrated because it prevented the enediyne to undergo Bergman cyclization.47 A
β-lactam-fused system with an in-built nucleophilic handle was also developed. In the presence of acid,
the β-lactam ring was opened by an intramolecular nucleophilic reaction to produce bicyclic reactive
enediyne. This assisted to activate the annelated ten-membered ring (Scheme 8.55).
The synthesis of 1,4-fused β-lactam-based enediyne was reported.48 In comparison to other ten-membered enediynes, β-lactam-fused enediyne surprisingly had a higher locking ability (Scheme 8.56).
8.3.8 Strategies Toward Fused β-Lactam Enediynes
Three approaches were studied for the synthesis of β-lactam-fused enediynes. These included the formation of enediyne onto a β-lactam system (path a),49 formation of β-lactam onto an enediyne system50 (path
b), and formation of both the enediyne and β-lactam systems51 (path c) (Schemes 8.57, 8.58, and 8.59).
1
i)
N
3
R
O
H2Cl; ii) AlEt2Cl.
SCHEME 8.52 Synthesis of disubstituted alkene.
X
N
O
Types of systems in which -lactam acts as a scaffold
N
R
1
R
R
N
3
R
X
NR
O
ii)
3
2
Al
NR
O
R
1
R
X
X
+
N
2
R
2
R
N
Al
3
R
NR
O
Al
SCHEME 8.53 Aspects of β-lactam as scaffold.
263Beta-Lactams as Synthons for Diverse Heterocycles
O
O
O
OH
H
H
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O
O
O
O
S
i)
O
N
O
S
S
+
O
N
O
(NOT OBTAINED)
O
O
S
C
C
O
N
O
O
S
S
O
O
O
O
S
C
C
O
S
i)
O
O
O O
CSC
+
O
O
O
SCHEME 8.54 β-Lactam ring prevents allene isomerization.
i)
O
O
H
CO
3
O
H3N
CO
3
HN
O
N
O
OH
N
DNA
OH
pH
+
O
=
7
H
CO
3
O
.
H
CO
3
O
O
H2N
N
H
N
HN
OH
OH
O
H
3
H
i) = mCPBA
CO
N
O
H2N
CO
3
HN
O
N
H
OH
O
O
.
SCHEME 8.55 Using β-lactam to prevent cyclization in enediynes.
8.3.9 β-Lactam Nucleobase Chimeras
The preparation of diverse cis- and trans-β-lactam nucleobase chimeras from the propargyl nucleobase
system and diphenyl nitrone was reported.52 The yield of nucleobase chimeric compounds was improved
via the formation of in situ Cu (I) acetylide from Cu(OAc)2 and L-ascorbate (Scheme 8.60).
8.3.10 Conformationally Restricted β-Lactam Peptides
A successful synthesis of scaffolds to induce β-turns is an important area of research. An efcient
turn mimetic requires alteration of native peptide structure. The crucial objective was to insert a
264 Chemistry and Biology of Beta-Lactams
O
O
O
HN
Ph
H
H
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N
SCHEME 8.56 Enediyne-fused β-lactams.
i) ii)
NH
HO
A
O
Cl
NH
OH
i) A, Pd(PPh
)4, CuI; ii) MsCl, NEt3; iii) K2CO3, DMF
3
SCHEME 8.57 Pathway “a” toward β-lactam-based enediynes.
EtOOC
i)
N
O
i) ClCOCH
COOEt, NEt3; ii) Tosylazide; iii) Rh2(OAc)4.
2
N
O
NH
O
iii)
N
O
OMs
EtOOC
ii)
N
2
_
N
O
iii)
O
N
EtOOC
SCHEME 8.58 Pathway “b” toward β-lactam-based enediynes.
n
O
O
N
i)
Ph
i) CuI, Et3N.
OH
O
N
i)
Ph
SCHEME 8.59 Pathway “c” toward β-lactam-based enediynes.
O
n
O
N
H
n = 0, 1
H
O
n
O
N
OH
H
H
Ph
H
O
N
Ph
O
N
Ph
265Beta-Lactams as Synthons for Diverse Heterocycles
H
O
3
O
O
O
O
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NN
N
2
SCHEME 8.60 Synthesis of β-lactam nucleobase chimera.
N
N
Ph
N
Ph
1
H
O
R
N
H
Maximum backbone
constraint
(random
O
Me
B
O
i) CuI,Et
H
N
-turn)
HN
i)
+
N, A, DMF.
O
N
H
N
Ph
Ph
Minimum
(CH
HN
HN
O
B
N
O
structure
change
+ HN CH2)
1
R
O
O
O
N
Ph
N
O
Ph
A
N
N
H
SCHEME 8.61 Energy-minimized structure, X-ray structure, and structural parameters in agreement with β-turn
peptidomimetics.
1
R
HN
SCHEME 8.62 Design of β-turn mimetic.
β-turn-inducing element, which can force the peptide backbone to participate in intramolecular H-bonds
between amino acids. Palomo et al.53 showed an efcient β-turn mimetic using a 1,3-disbstituted β-lactam
H
2
R
N
O
O
NOH
1
R
N
N
O
NOH
1
R
N
N
H
O
N
as the backbone. They synthesized pseudopeptides containing optically active β-amino-β-lactam fragments. The geometries of the compounds were proved by X-ray crystallography in the solid state. It was
shown that the alkylamino substitution pattern of β-lactam rings was placed as residues in tetrapeptide
systems. The syn-disubstitution did not create a stabilization, while anti-disubstitution was suitable with
β-turn formation. The N- and C-terminal residues in tetrapeptide models had minimum effects (Scheme
8.61).
The synthesis of azetidinyl β-lactam-based peptides54 was reported. The trans-disubstituted β-lactam
demonstrated an intramolecularly H-bonded structure.80 The cis-isomers did not demonstrate any
well-dened intramolecular H-bonding, indicating their conformational exibility. The cis- and transβ-lactam tripeptides were synthesized via Kinugasa reaction using propargyl-substituted ethyl pyroglu-
tamate and diphenylnitrone as the starting compounds (Schemes 8.62 and 8.63).
266 Chemistry and Biology of Beta-Lactams
O
2
3
O
R
2
Et
2
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Ph
N
H
Ph
2
2
Ph
Ph
i)
Et
H
O
O
iv)
H
N
CO2CHPh
O
Ph
CO
N
O
NHPh
N
Ph
N
O
Ph
2
O
O
i) KOH, TBAB, propargyl bromide, THF; ii) Et
CO
N
H
CO
N
N
O
iv)
O
N
N
O
ii)
Et
2
O
N
O
H3N
CO2CHPh
B
Ph
HPh
N
Ph
O
A
N, CuI, A, CH3CN; iii) LiOH, THF-H2O; iii) EDC.HCl, B, HOBt, DMAP.
CO
N
Ph
2
Ph
+
O
Et
2
N
O
R
R = H
O
N
O
O
N
O
=
CO
N
O
O
N
+
R
O
2
Ph
Ph
Et
N
H
Ph
N
Ph
N
H
Ph
Ph
N
O
iii)
H
N
O
+
H
N
CO2CHPh
O
Ph
R
CO
2
Ph
N
Ph
=
R
Et
R = H
CO2CHPh
Ph
2
SCHEME 8.63 Synthesis of cis- and trans-peptides.
1
R
O
1
N
S
Ph
O
R
1
ClOC
R
1
COCl
R
R
O
1
1
i) R
i)
2
NH
O
O
Et
N
2
R
R
1
R
1
O
N
O
R
O
N
2
R
SCHEME 8.64 4-Oxo-β-lactam as HLE inhibitor.
8.3.11 4 -Oxo - β-Lactams as Scaffolds for Elastase Inhibitors
Suitably substituted β-lactams were used as inhibitors for human leucocyte elastase (HLE). For example,
the use of 4-oxo-β-lactam55 for elaborating as HLE inhibitors was reported. The design was possible due
to an earlier report56 on 4-oxo-β-sultam as inhibitor of porcine pancreatic lipase (PPE). The inhibition
of elastase was possible through the expulsion of the sulfonamide group. The selectivity was improved
using a weaker leaving group such as an amide. It was seen that isosteric analogues of 4-oxo-β-lactams
retain the inhibitory activity. Docking studies indicated efcient non-covalent interactions of the inhibitor with the enzyme (Scheme 8.64). Thus, the application of β-lactams for the synthesis of numerous
heterocycles has received signicant attention. In a seminal publication, Basak et al. demonstrated the
use of β-lactams as starting materials for the preparation of diverse heterocyclic compounds.
57
267Beta-Lactams as Synthons for Diverse Heterocycles
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8.4 Conclusion
β-Lactams are probably the most privileged heterocyclic systems in the broad domain of chemistry, biology, pharmacy, and clinical medicine. They are also important synthetic intermediates toward numerous
bioactive and structurally diverse heterocycles. Some β-lactams have also been explored as structural
scaffolds to tune, modulate, or mimic the reactivity of other bioactive compounds. The reliability and
popularity of β-lactam synthon method are also signicant. Importantly, asymmetric synthesis of
β-lactams and diverse heterocycles can be made using a variety of methods.
Acknowledgments
AD is grateful to CEA-Grenoble, Joseph Fourier University, University of Göttingen, and University
of California, Los Angeles, for their support. BKB is grateful to the US NIH, the US NCI, Texas
Kleberg Foundation, Stevens Institute of Technology, University of Texas M.D Anderson Cancer
Center, University of Texas-Pan American, University of Texas Health Science Center (San Antonio),
and Community Health Systems of Texas for their competitive support to his research. AD and BKB
acknowledge support from their current employer, Prince Mohammad Bin Fahd University. The authors
are grateful to Professor Amit Basak for his tremendous contribution in this subject.
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54. (a) Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.; Fratila, R. M.; Matute, C.; Domercq, M.;
Gago, F.; Martin-Santamaria, S.; Linden, A. J. Am. Chem. Soc. 2003, 125, 16243. (b) Palomo, C.;
Aizpurua, J. M; Ganboa, I.; Benito, A.; Cuerdo, L.; Fratila, R. M.; Jimenez, A.; Loinaz, I.; Miranda,
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Applications, Springer Book Chapter, 2017, 373 – 419.
9
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Medicinal Activities of Beta-Lactams as
Antibacterials and Their Mechanism of Action
Aparna Das1 and Bimal Krishna Banik
1
Department of Mathematics and Natural Sciences, College of Sciences and Human Studies,
2
Prince Mohammad Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
2
Department of Mathematics and Natural Sciences, College of Sciences and
Human Studies, Deanship of Research Development, Prince Mohammad
Bin Fahd University, Al Khobar 31952, Kingdom of Saudi Arabia.
*Corresponding authors: Aparna Das, email: aparnadasam @gmail .c om;
BimalKrishna Banik, email: bimalbanik10 @gmail .c om; bbanik @pmu .edu .sa
9.1 Introduction
The beta-lactam antibiotics are currently the most important antibacterial agents in the arsenal of agents
used to treat infectious diseases at present. In the United States, beta-lactam antibiotics account for more
than 65% of all prescriptions for injectable antibiotics. Among all beta-lactams, cephalosporins account
for nearly half of all prescriptions for beta-lactams (Tabl e 9.1). There are a number of beta-lactams that
are well tolerated and are effective and widely prescribed.
A small but signicant part of the toxicity of penicillins and cephalosporins can be attributed to the
development of an allergic reaction due to similar side-chain determinants; notably, such reactions are
most prevalent with penicillins and cephalosporins, while monobactams are least reactive.1, 2 When it
comes to treating serious infections, beta-lactams are considered to have a major advantage over other
antibiotics as they possess a bactericidal mechanism of killing. Due to the rapid emergence of betalactamases against these agents, beta-lactamase-stable agents were developed in an effort to counteract
this threat, as well as potent beta-lactamase inhibitors (BLIs).
We have conducted synthesis and biological evaluation of diverse organic compounds including
beta-lactams.
compounds in chiral forms is achieved by employing carbohydrates, enzymes, and asymmetric metalassisted methods.
tures.
To accelerate the process and follow environmentally benign methods, microwave-mediated reactions
are performed.
and many of these are considered anticancer agents.
organocatalysis are followed to prepare diverse compounds with anticancer activities.
this chapter, the most commonly available beta-lactam antibiotics (such as penicillins, cephalosporins,
carbapenems, and monobactams) are presented.
3–8
Many of these compounds are linear or cyclic in nature.
20–24
25–27
Some organocatalytic routes are used to synthesize molecules with antitumor properties.
Studies on physical parameters help to design potent biologically active struc-
32–46
We have shown the application of tellurium for the preparation of organic molecules,
47–58
A number of environmental methods including
9–19
Synthesis of some of these
25–28, 59–67, 68–74
28–31
In
9.2 Mechanism of Action
As a result of covalent binding to essential penicillin-binding proteins (PBPs), beta-lactam antibiotics
act as bactericidal agents that interrupt the formation of bacterial cell walls, which are critical enzymes
DOI: 10.1201/9780367816339-9
269
270 Chemistry and Biology of Beta-Lactams
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TABLE 9.1
Usage of Parenteral Β-Lactams by Class from 2004 to 2104 in the United States
Class of β-lactam Percentage of prescriptions
Cephalosporins 47.49
Broad spectrum penicillins
Carbapenems 11.20
Narrow-spectrum penicillins 3.12
Monobactams 1.66
a
The percentage for each injectable antibiotic class prescribed in the United States from
2004 to 2014. (Data from the IMS MDART Quarterly Database on le at AstraZeneca).
b
Broad-spectrum penicillins include the β-lactam/β-lactam-inhibitor combinations piperacillin–tazobactam, ticarcillin–clavulanate, and ampicillin–sulbactam.
b
36.54
a
involved in the terminal steps of peptidoglycan cross-linking in both Gram-negative and Gram-positive
bacteria. As each bacterial species has its own unique set of PBPs, they can range from three to eight
enzymes depending on the species.75 Tipper and Strominger published a classical paper in which they
describe how penicillin inhibits the transpeptidation of bacterial peptidoglycans mechanistically.76 They
noted that penicillin G has a structural similarity with the terminal d-Ala-d-Ala dipeptides that form the
nascent peptidoglycans in a dividing bacterial cell.
It is now known that this mechanism involves the binding of penicillin, or another beta-lactam, to a
serine in the active site of all functional PBPs.77 It is possible that the inactive acyl enzyme produced
by the process may then slowly hydrolyze the antibiotic in order to form a microbiologically inactive
product.78 Recent work on beta-lactams, such as ceftaroline, has demonstrated that these compounds
bind to an allosteric site in a cell surface protein called PBP2 in S. aureus and lead to an increase in the
susceptibility of the organism to antibiotics.
PBPs can be classied according to their molecular mass,
79, 80
81, 82
with low-molecular-mass PBPs serving
mainly as monofunctional d-Ala-d-Ala carboxypeptidases. One of the main functions of high-molecularmass PBPs consists of two subclasses: the rst (class A) consists of bifunctional enzymes with both
transpeptidase and as transglycosylase domains, and the second (class B) comprises transpeptidases
which are dependent on d-Ala-d-Ala. At least one PBP is deemed to be essential in each species, with a
unique specicity for beta-lactam binding that varies among each species and each beta-lactam class.83
In Gram-negative bacteria, essential PBPs include the high-molecular-weight PBPs 1a and 1b that are
involved in cell lysis; PBP2, the inhibition of which results in a cessation of cell division and the formation of spherical cells; and PBP3 for which inhibition arrests cell division, resulting in lamentation. If
one or more of these PBPs are inhibited, cell death may occur as a result of the inhibition.84 There is a
detailed discussion of the roles of PBPs in Gram-positive bacteria, as well as M. tuberculosis.
85
9.3 Antibacterial Activities of Cephalosporins
A cephalosporin is a class of beta-lactam antibiotics that are derived from the fungus Acremonium,
which was formerly known as Cephalosporium (Fig u re 9.1). As a group with cephamycins, they are
considered to be a subgroup of beta-lactam antibiotics known as cephems. Cephalosporin was rst discovered in 1945, and its rst sales took place in 1964.86 In general, substitutions at position 3 affect the
pharmacology of the drug; substitutions at position 7 affect the antibacterial activity of the drug, but this
is not always the case.
Cephalosporin antibiotics can be prescribed for the prophylaxis and treatment of infections caused
by bacteria that are susceptible to this particular form of antibiotic. A majority of the rst-generation
cephalosporins are active against Gram-positive bacteria, such as Staphylococcus and Streptococcus.
Therefore, they are mostly used in the treatment of skin and soft tissue infections, as well as the prevention of hospital-acquired surgical infections.87 Over time, successive generations of cephalosporins have
271Medicinal Activities of Beta-Lactams as Antibacterials
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FIGURE 9.1 Core structure of the cephalosporin antibiotics.
increased their activity against Gram-negative bacteria, even though they have often reduced their activity against Gram-positive organisms. Due to the different structure of the beta-lactam antibiotics, the
antibiotic may be used in patients who are allergic to penicillin. It is possible for the drug to be excreted
in the urine after it has been taken.
Cephalosporin therapy is associated with a number of adverse drug reactions (ADRs) that may include
diarrhea, nausea, rash, electrolyte disturbances, as well as pain and inammation at the injection site.
ADRs that are uncommon include vomiting, headaches, dizziness, vaginal and oral candidiasis, pseudomembranous colitis, superinfections, eosinophilia, nephrotoxicity, neutropenia, thrombocytopenia, and
fever.
A cephalosporin is a beta-lactam antibiotic that is bactericidal, and, as with other beta-lactam antibiotics, it disrupts the synthesis of the peptidoglycan layer that makes up the bacterial cell wall. In order to
maintain the structural integrity of the cell wall, the peptidoglycan layer is important. During the process
of synthesizing the peptidoglycan, the nal step of transpeptidation is carried out by PBPs. It is known
that PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) in order to
cross-link the peptidoglycan. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby irreversibly
inhibiting PBP cross-linking of peptidoglycan.
76
There are different ways in which the nucleus of cephalosporin can be modied in order to gain different properties. Depending on the antimicrobial properties of a cephalosporin, they can be grouped into
“generations”. It should be noted that the rst cephalosporins were classied as rst-generation cephalosporins; however, later, more extended-spectrum cephalosporins were classied as second-generation
cephalosporins. It is a well-known fact that each newer generation has greater Gram-negative antimicrobial properties than the preceding generation, and, in most cases, their activity against Gram-positive
organisms has decreased as well. There is, however, a true broad spectrum of activity with the fourthgeneration cephalosporins.
Since the discovery of the naturally occurring penicillinase-resistant cephalosporin C in the 1950s, a
new path has been opened to the development of hundreds of novel cephalosporins, which are used to
treat infections caused by the major penicillinase-producing pathogen of medical interest at that time, S.
aureus, which has been known for centuries.
88, 89
As a result, there are several hundred cephalosporins in
clinical practice, either as parenteral or as oral medications. Minimum inhibitory concentrations (MICs)
of these molecules were often as low as 4 µg/mL, indicating antibacterial activity not only against staphylococci, but also against S. pneumoniae, as well as bacteria that do not produce beta-lactamase. In a lot
of cases, it was found that the parenteral agents had a potency eightfold higher than the oral agents, which
could be used in some cases as a replacement for oral penicillins in patients with penicillin allergies.
In the early days of cephalosporins, such as those in the cephalosporin I subclass,90 introduced before
1980, many of them were susceptible to hydrolysis by the beta-lactamases that emerged as a result of
their introduction into clinical practice. As a result, only a few of these molecules remain in use, primarily for treating mild-to-moderate skin infections caused by methicillin-resistant S. aureus (MSSA).91 For
surgical prophylaxis and to treat abdominal infections92 (Tables 9.2 –9.4), cefazolin is effective as a rstline treatment in 80% of Japanese children who suffer from their rst upper urinary tract infection 93.
As soon as the transmission electron microscopy (TEM)-1 penicillinase was found on transmissible
plasmids in N. gonorrhoeae94 and H. inuenza,95 the medical community quickly recognized that the
penicillins and cephalosporins in use were becoming increasingly ineffective, not only in treating those
organisms that produced TEM-1, but also in treating enteric bacteria and P. aeruginosa, which had the
potential to acquire this enzyme. Cephalosporins, which are applied both topically and parenterally, are
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