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62 Chemistry and Biology of Beta-Lactams
Ph
OMe
OMe
2
2-thienyl, 2-naphthyl;
-NHCH(Ph)
CH(Ph)
-(CH2)
Me
Me
O
,
6
4
6
4
6
4
6
4
6
4
e
c
https://t.me/med1917
Ph
MeO
HO
6
H
S
O
OMe
H
4-ClC
,
4
,
O
N
O SMe
O
O
O SM
H
2-BrC
,
4
6
OA
N
H
4
6
O
Cl
N
O SMe
O
N
O S
=
R
2-FC
3-BrC
H
3-FC
,
4
6
H
4-BrC
,
FIGURE 2.9 N-thiolated β-lactams.
O
Cl
N
O SMe
MeO
Cl
R
N
O SMe
H
6
4
H
4-FC
,
,
2-IC
H
4
6
H
2-ClC
,
3-IC
,
H
3-ClC
,
4
6
H
4-IC
,
S
Ph
N
O
2
S
R
N
H
O
7
R
S
N
H
O
1
=
R
SO
2
2,4-Cl
Me,
C
6
H
,
2
4-MeC
R
;
5
4-NO
6
=
OCOC
3-CF
,
2
H
,
4
6
2-naphthyl;
H
6
4-CF
,
3
8
R
OCONHC
,
5
,
3
=
-NHCH
R
3,5-(CF
FIGURE 2.10 Alkyl/arylt hio -substituted β-lactams.
O
S
N
O
S
N
O SO
H
3
S
N
O
SO
3
2
=
H,
OH, SH;
7
=
R
H
;
H,
5
6
,
2-OMe, 3-OMe, 4-OMe,
)
2
3
Ph,
2
3
R
2-F,
,
2
7
R
=
H, Et;
4-F,
-
NHCH
1
R
SO
S
2
N
O
COOCH(Ph)
4
R
2
R
3
R
O
5
R
N
6
R
7
R
S
N
8
R
O
R
3,4-F
2
4
=
,
2
5
=
R
H, Et;
2-Cl-4-F, 3-Cl-4-F,
,
3,4-(OMe)
,
2
4-SMe,
2
C
3
CH
t-butylacetyl and (R)-1-phenylpropionyl urea. In order to reduce the molecular weights of these compounds, the peptidic moiety was changed with non-peptidic systems, which gave non-peptidic β-lactams
good inhibitory activity. For example, β-lactams with a phenyl group at C4 demonstrated IC50 value of
1.9 μM. Addition of methylene groups between C4 phenyl and β-lactam core reduced the inhibitory
power. The presence of C3 methyl group enhanced the activity.
Veinberg et al.26 synthesized 4-sulfonylazetidin-2-ones, 4-sulfonylthioazetidin-2-ones and 4-sulfothioazetidin-2-ones. These were tested against various cancer cells (human brosarcoma, mouse hepatoma,
63Monocyclic Beta-Lactams
https://t.me/med1917
mouse melanoma, and mouse neuroblastoma). The results demonstrated that compounds with methylsulfonylthio, 4-met hoxyc arbon ylami nophe nylsu lfony lthio , and 4-tolylsulfonylthio substituents in 4-sulfonylthioazetidin-2-ones demonstrated excellent anticancer activities. A denite relationship between
cytotoxic concentration and intensity of NO radical generation was advanced.
A series of monocyclic 4-ary lthio /alky lthio /alky ldisu lde -β-la ctams were prepared by Kostova et al.27
These compounds were evaluated for antibacterial activity against M. tuberculosis and M. catarrhalis.
The results showed that some compounds were active against β-lactamase-producing strain and inactive against other non-β-lactamase-producing bacterial strains. The N-unsubstituted β-lactam thioethers
showed higher bioactivity than N-sulfonated β-lactams. Two β-lactams demonstrated best antimicrobial
activity against M. tuberculosis and M. catarrhalis, respe ct ive ly.
Clemente et al.28 designed and synthesized N-acyloxymethyl and N-aminocarbonyloxymethyl derivatives of β-lactams 90. These compounds were tested for human leukocyte elastase (HLE) inhibitory
activity. A substitution at position C3 was able to increase the potency. The C3 gem-diethyl group helped
to increase activity signicantly. In addition, sulfone derivatives were found to be better than sulde
derivatives. β-Lactams with C3 gem-diethyl group and C4 phenyl sulfone group demonstrated highest
potency.
Novel 4-arylthioether-2-azetidinone derivatives as non-transpeptidase, β-lactamase inhibitors
were prepared and evaluated by Beck et al.29 All these β-lactams showed inhibitory activity against
β-lactamases-producing M. tuberculosis and M. catarrhalis. Importantly, β-lactam derivatives with carbamyl group at N1 showed good activity along with electron-withdrawing groups on arylthioether moiety. Additionally, presence of CF3, F, and Cl (o or p) on aromatic ring of arylthio moiety demonstrated
antibacterial activity. The activity was diminished when aryl group on C4 thioether was replaced with
allyl and urea at N1 was replaced with carbonyl group.
Galletti et al.30 designed, synthesized, and evaluated a series of integrins (αvβ3 and α5β1) targeting
β-lactam derivatives. In all the β-lactams, carboxylic and amine terminals are located at a considerable distance (9–14 atoms apart) in order to turn on the recognition capability by integrins. The adhesion ability of β-lactams towards immobilized bronectin was evaluated against K562 and SK-MEL-24
cells. The β-lactams exhibited concentration-dependent augmentation in bronectin-mediated adhesion
of K562 and SK-MEL-24 cells. In addition, a β-lactam acid was found to be selective for α5β1 (EC50 12
nM), while another amino acid compound showed superior afnity towards αvβ3 (EC50 11 n M).
Aoyama et al.31 designed and synthesized benzylazetidin-2-one analogue and investigated pharmacological evaluation for human chymase inhibitory activity. Structure–activity relationship studies identied a molecule with enhanced stability in human plasma and excellent chymase inhibitory activity (IC50
3.1 nM). It was suggested that stability in human plasma was inversely proportional to the chymase
inhibitory activity.
Gerona-Navarro et al.32 synthesized phenyl alanine-derived 1-acyl-2-azetidinones and 1-acylazetidines. These compounds were screened for anti-human cytomegalovirus (HCMV) activity. The 1-acyl2-azetidinones were active against HCMV in HEL cell cultures. The results demonstrated that free
carboxylic acid has negligible activity. Further, a molecule showed antiviral activity amongst β-lactam
series against AD-169 and Davies strains (EC50 11 and 13 μM). Importantly, 1-acylazetidines exhibited
inhibitory activity (EC50 0.74 and 0.62 μM) comparable to the standard compounds, i.e., ganciclovir
(EC50 0.9 and 0.8 μM) (Fig u r e 2 .11).
Feledziak et al.33 reported the synthesis of 2-azetidinones and studied human fatty acid amide hydrolase (hFAAH) inhibition. A β-lactam was identied for this purpose (IC50 3.65–5.56 nM), and it showed
a noncovalent interaction between hFAAH and the substrate. Analyses of different synthesized compounds in this series suggested that Log P values and polar surface area can be adjusted without changing FAAH inhibition. Moreover, the inhibitory activity was not changed due to the modication of
solubility and permeability.
Adlington et al.34 conducted synthesis of monocyclic β-lactams as inhibitors of prostate-specic antigens (PSAs). This study resulted in the identication of a β-lactam as PSA inhibitor (IC50 0.348 ± 0.05
μM). Asymmetric synthesis of this compound afforded enantiomerically pure (3S,4S) form with better
inhibitory power (IC50 0.226 ± 0.01 μM).
64 Chemistry and Biology of Beta-Lactams
O
O
Bz
X = O, NH
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Ph
N
O
X
HO
O
O
Ph
O
N
O
O
O
Ph
CH
2
t
Bu
COO
N
O
O
Bz
FIGURE 2.11 N-acyl-β-lactams.
O
O
Burnett et al.35 synthesized a series of monocyclic β-lactams which are conformationally restricted
analogues of ACAT inhibitors
31b
(SA 58035 and CI 976). Racemic and chiral forms of trans-β-lactam
were synthesized and evaluated for cholesterol absorption inhibitory (CAI) activity. The β-lactam with
phenyl and 2,4,6-trimethoxyphenyl groups at C4 and N1 demonstrated better in vitro activity in comparison to in vivo. A loss of CAI activity was observed with molecules that have no substitution at C4 of
the ring. Importantly, trans-2-azetidinone (IC50 18 μM) demonstrated better activity than its cis-isomers.
The compound with a positive optical rotation was double active than the compound that had a negative
rotation.
Clader et al.36 synthesized β-lactam cholesterol inhibitor by modifying different side chains. It was
found that N1 aromatic group is crucial for the activity. The nature of different substitutions on aromatic
group did not alter the activity too much. The presence of a methoxy or a similar H-bonding group on
C4 phenyl group and phenylalkyl substitution at C3 was crucial for the activity. Importantly, the length
of the C3 group played a role in CAI. Results showed that a few β-lactams inhibit the accumulation of
esteried as well as unesteried cholesterol (Fig ure 2 .12).
A series of carboxy-substituted β-lactams as potential CAI were designed and synthesized by Vaccaro
et al.37 It was suggested that the heteroatom at fourth position of the C4 aromatic substituent is not
crucial. A number of carboxy groups were introduced at the para position of the C4 aryl group, which
resulted in the improvement of CAI function.
Rosenblum et al.38 prepared a series of C3 unsaturated and saturated β-lactams and evaluated them
for CAI activity. 3-Arylpropenyl- and 3-arylpropynyl-substituted β-lactams were synthesized via
Pd-catalyzed arylation of alkenes/alkynes followed by catalytic hydrogenation. The tests on these
β-lactams showed that both unsaturated and saturated analogues have CAI activity. In addition, β-lactam
with a C3 allyl group demonstrated that low CAI activity conrms the importance of a pendent phenyl
residue on C3 site (Fig u re 2.13).
A few active metabolites of β-lactam were identied by Heek et al.39 For this work, the authors used
bile duct and intestinally cannulated rat models. The C4 phenol was found to be the most active metabolite, and modication of this molecule resulted in identication of a potent compound with CAI activity.
The ID50 of these compounds in rat model was calculated as 0.0015 mg/Kg and 0.05 mg/Kg. Importantly,
a dose–response study demonstrated that an active β-lactam was about 400 times more potent than
another active compound in this series.
Rosenblum et al.40 synthesized an orally active 2-azetidinone by considering potential metabolism
sites. The SAR studies were focused on investigating the effects of aromatic hydroxylation and benzylic
oxidation of the C3 side chain on CAI activity. The effects of uorine on various inhibitors were also
investigated. The presence of p-OH or dihydroxy in the aromatic group of the C3 side chain lowered the
CAI activity. Further, 3S benzylic OH group on C3 side chain of β-lactam demonstrated better CAI activity than the 3R isomer. In case of C3 side chain, ketone demonstrated activity. Importantly, uorine group
was introduced because of its small bulk and less steric nature. This led to the discovery of a unique
compound, 1-(4-uorophenyl)-(3R)-[3-(4-uorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2azetidinone (SCH 58235). This β-lactam was successful in lowering total plasma cholesterol level in
humans and showed a 50-fold increase in CAI activity in comparison to its optical isomer.
39
65Monocyclic Beta-Lactams
OMe
Ph
R
5
e
6
4
F
R
3
OH
F
R
4-Cl
6
6
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N
O
OMe
7
R
N
O
1
2
=
R
4-NMe
,
2
2
2O)2
6
=
,
3,4-(OCH
,
H
2-CH
,
4
H
H,
Ph(CH
4-NHCOCH
,
2
3,4-(Me)
OHC
2
2O)2
3)3
,
R
;
2
H
6
;
3,4-(OH)
5
4
R
NH
OMe)
OH, 4-Cl, 4-CN, 4-MeSO,
(OCH
OHC
COOHC
FIGURE 2.12 3-Alkylated β-lactams.
OH
OMe
3
R
,
3
=
4-CF
,
OH
2
R
1
R
N
O
8
R
N
O
=
H,
4-OMe, 3-OMe, 4-OPh, 4-OH,
4-OHCH
4-MeSO
CH
4-CH
,
2
2
COOMe,
2
H
3C6
4-PhCH
,
2
OCH
3
,
4-Me,
CH
4-COOHC
,
4
2
R
O,
2
R
;
2
3-NH
COOH,CH=CHCOOMe;
2
3
R
Ph
4
R
O
OMe
8
R
O
4-NO
n
4-
Pr,
4
=
H,
4-CH
,
2
R
H
;
4
6
4-F,
n
i
4-
4-
PrO,
PrO,
4-OMe, 3-OMe, 2-OMe, 4-OPh,
4-OCF
CO,
3
8
=
2-OHC
,
3
6
R
H
,
4
6
N
N
,
4-SH,
2
n
4-
BuO,
2,4,6-(OMe)
=
F,
OMe;
OHC
4-CH
2
OH
4-Me,
t
4-
BuO,2,4-
HO
6
R
OM
4-
4-
,
3,4-
3
7
=
R
24-
H
,
4
6
N
O
OH
F
OH
1
R
O
OH
F
N
O
F
O
I
OH
O
H
N
O
OH
O
F
O
F
1
=
H,
OH,
H
C
2
=
R
F;
H,
Ph,
=O, OAc;
4-OMeC
6
=
R
;
4
3
=
R
H
OH, OMe, OAc, OBn;
4
FIGURE 2.13 Hydroxyalkyl and modied alkylated β-lactams.
N
N
N
4
R
CF
3
=
OMe, OH,
4
R
F
OMe
OH
O
N
F
OMe
H
F
N
O
OMe
6
F;
O
5
R
N
H
5
=
R
4-MeC
N
R
O
H
,
4
6
66 Chemistry and Biology of Beta-Lactams
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Some structural modications were performed on C4 aryl substituent of a potent CAI agent by Vaccaro
et al.41 It was found that β-lactam with 2’,4’-dimethoxyphenyl at C4 demonstrated CAI activity, while
2’,4’,6’-trimethoxyphenyl compound was inactive. An introduction of a hydroxyl group enhanced the
CAI potency. The most potent β-lactam (ED50 0.005 mg/Kg/day) with 2’,4’-dihydroxyphenyl substituent
at C4 was found to be 440 times more active than other compounds.
Burnett et al.42 synthesized a series of radioiodinated β-lactam analogues as enantiomers. These synthesized radioiodinated analogues were screened for in vivo CAI activity. The tests identied a few compounds. Some of these β-lactams were biochemical tools for binding and localization studies.
Liu et al.43 reported the synthesis of chiral C4 triuoromethyl-substituted trans-β-lactam derivatives as
analogues of ezetimibe. Cholesterol absorption inhibitory effects of these β-lactams were investigated in
Caco-2 cells. It was suggested that 4-CF3-β-lactam demonstrated inhibitory activity like ezetimibe. But
replacement of other groups reduced the CAI activity.
Mckittrick et al.44 prepared a series of β-lactams by carrying out alteration at the C3 side chain to
investigate the CAI activity. For this reason, 1’-hydroxyl group was added on C3 side chain. It was found
that an (S)-conguration at C4 is necessary.31 Interestingly, this study identied the rst example of cis1’(R)-β-lactam derivative (ED50 0.4 mg/Kg/day), which showed higher activity in comparison to transisomer. Moreover, this β-lactam was also more active than deshydroxy analogue (ED50 4 mg/Kg/day).
Kirkup et al.45 prepared 2-azetidinone based on reported SAR studies.31 The authors modied the
C1’ and C3’ positions of β-lactams and incorporated electron-withdrawing uorine at N1 aryl group.
Cholesterol-fed hamster model-based evaluation indicated 1’-(S)-trans-β -lactam (SCH 57939) with high
potency and enhanced metabolic stability. The increased metabolic stabilities were due to the replacement of labile p-methoxyphenyl at N1 and C4 with F and OH, respectively.
A series of 2-azetidinone derivatives were prepared and screened for CAI activity by Dugar et al.46
On the basis of metabolism study, aryl group on C3 was modied by changing different p-substituted
groups. It was found that p-uoro analogue showed maximum CAI activity in cholesterol-fed hamster
model. Further, cholesterol-fed hamster and rhesus monkey assay identied equipotent molecules with
high metabolic stability.
Huang et al.47 have synthesized 14 β-lactam derivatives for CAI activity in rats. The polarity of the
ezetimibe analogues was increased by introducing amide group in C3 position. In addition, additional
phenyl groups were added to improve the hydrophobicity for better drug–receptor interactions. The CAI
activity was measured in cholesterol-fed hamster model. The results were compared with ezetimibe.
A stereocontrolled synthesis of N-polyaromatic-substituted β-lactam derivatives was described by
Banik et al.48 All the products were obtained in trans-conguration. These β-lactams were tested for
anticancer activities against nine cancer cell lines, and results were compared with clinically active
medicine, cisplatin. The results demonstrated that phenanthrene- and chrysene-substituted 3-acetoxy-
β-lactams were equipotent to cisplatin against breast cancer cell line. In case of colon cancer cell line,
β-lactam was found to be three times more potent than cisplatin. Further, naphthalene, anthracene, and
pyrene derivatives showed a very low anticancer activity, while 3-phenoxy- and 3-phthalimido-β-lactams
were inactive. In case of ovarian cancer cell line, the potent β-lactam and cis-platin exhibited similar
anticancer activity.
In continuation of the above work,49 Banik et al. developed a strategy for asymmetric synthesis of
N-polyaromatic-substituted 2-azetidinones using chiral carbohydrates as ketene precursors. Optically
active β-lactams were tested against several human cancer cell lines for anticancer activity using cis-
platin and a racemic anticancer β-lactam as positive controls. This study demonstrated that optically
active β-lactam, the positive isomer, is more potent than the racemic β-lactam. Further, the isomer that
had negative rotation exhibited reduced anticancer activity than the isomer which had positive optical
rotation (Figure 2 .14).
Sun et al.50 synthesized 1,4-diaryl-substituted 3-acetoxy/hydroxy-2-azetidinones as conformationally
restricted combretastatin A-4 (CA4) analogues. These β-lactams were tested against various normal
and tumor cell lines for cytotoxicity. Some of these β-lactams showed cytotoxic activities against various cancer cell lines in comparison to normal cells. The best results were observed for β-lactams with
p-methoxyphenyl, 4-methoxy-3-nitrophenyl, and 4-methoxy-3-aminophenyl substituents at C4 (IC50
25–74 nM) against human neuroblastoma cells. Further, a β-lactam was tested for inhibitory effects
67Monocyclic Beta-Lactams
R
NO
OMe
R
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AcO
Ph
N
O
NH
HO
N
O
OMe
1
=
H,
H
C
2
6
4
=
OMe;
4-F
,
4
2
=
R
H,
OH;
H
3-Me
C
,
4
6
,
FIGURE 2.14 3-Oxo-derived β-lactams.
2
OMe
OMe
OMe
R
C
R
3
=
H
4
6
5
=
AcO
O
2-ClC
,
3,4-(OMe)
Ph
,
6
HO
H
N
O
3-OMeC
,
4
C
2
Ph
N
6H3
2
R
OMe
H
4
6
OMe
OMe
1
R
4-OMeC
,
AcO
H
6
O
R
4
5
2-NO
,
HH
4
R
O
N
3
R
O
H
4-
C
,
4
2
6
on tubulin polymerization and found to show IC50 value of 5 μM. These results were also veried by
molecular modeling studies. The active β-lactam was found to be effective against rat pancreatic tumor.
The presence of 3,4,5-trimethoxyphenyl ring at N1 in β-lactams was essential for activity.
Tripodi et al.51 reported the synthesis of 1,4-diaryl-substituted 3-hydroxy/amino-azetidin-2-ones.
These compounds were screened for antiproliferative activity and studied for apoptosis induction as
well as for cell cycle effects. It was found that racemic and (+)-form of trans-β-lactam showed maximum
cytotoxicity (IC50 3–13 nM) against duodenal adenocarcinoma cells. This was also active against various
colon cancer cell lines. The antiproliferative activity was induced by tubulin polymerization inhibition
followed by G2/M arrest leading to apoptosis.
Jarrahpour et al.52 carried out diastereoselective asymmetric synthesis of β-lactams with exclusive formation of the cis-isomer. The double asymmetric induction resulted in complete cis-diastereoselectivity
via cycloaddition between chiral ketene and chiral imine. These β-lactam derivatives were screened
against P. falciparum (K14 resistant strain) for antimalarial activity. Some of them showed moderate to
excellent antimalarial activity (IC50 8–50 μM). In addition, β-lactams having 4-methoxyphenyl, 4-bromophenyl, 3,4-dimethoxyphenyl, and naphthyl showed excellent antimalarial activity (IC50 ≤11 μM) in
comparison to that of chloroquinine (IC50 11 μM).
A series of 3-acylamino-β-lactams were prepared and tested for inhibitory activity against cysteine proteases (cathepsins B, K, L, and S).53 These β-lactam derivatives showed better potency against
cathepsins L and K. They were also selective inhibitors of cathepsins (papain type) as compared to
serine proteases. It was also seen that compounds with OR, OPh, OCOR, and SPh at C4 demonstrated
inhibitory activity. Moreover, in case of alkoxy substituents, linear groups showed better results. The
stereochemistry of the C4 substituent affected the inhibitory activity. For example, the C4 phenylthio
group with trans-isomer was more potent, while C4 phenoxy group with cis-conguration showed better
activity. The most potent β-lactam derivative exhibited IC50 values in subnanomolar range (IC50 0.1 nM
against cathepsin L) (Figu r e 2.15).
68 Chemistry and Biology of Beta-Lactams
CbzH
CH
Ph
R
3
2
OPh, -CH=CHPh;
OH
https://t.me/med1917
2
H
N
O
F
F
O
O
1
=
2
=
R
H,
N
O
O
OH
OH
N
H
Cbz
N
H
3
=
R
CH
;
S
NH
O
O
HN
Ph, Bz,
Ph
H
N
NH
O
OH
OH
O
H
N
O
O
-CH
H
1
N
R
O O
O
H
3
R
N
O
O
EtOOC
CH
3
N
OCH2COOH
NH
O
Ph
N
+
4
R
Ph
O
OH
Ph
F
O
R
OH
N
H
H
(NH
2
=
OH
H,
CO)
NH
3
2
H
H R
N
4
O
H
O
N
H
N
O
H
N
O
H
O COOH
N
F
N
COO
Cl
-
FIGURE 2.15 3-Amino/acylamino-derived β-lactams.
Setti et al.54 synthesized and evaluated a series of 3,4-disubstituted β-lactams for inhibitory activity
against various cysteine proteases. A few such compounds exhibited excellent selectivity for different cathepsins. Importantly, β-lactam with C4 phenoxy group in trans-orientation demonstrated better
potency with no effect on selectivity. However, another β-lactam from this group was found to be selective for cathepsin K with IC50 value of 0.38 μM (IC50 for B, L, and K is 140, 3.4, and 33 μM). On the basis
of P2 element study, it was disclosed that cyclic moieties are essential P2 elements, and it had a crucial
role towards selectivity (mainly Cat L and Cat S).
Woulfe and Miller55 reported the synthesis and antimicrobial evaluation of [(3(S)-(ac ylami no)-2 -oxo-
1-aze tidin yl)ox y]ace tic acid derivatives. The antibacterial activity was screened against Gram-positive
and Gram-negative bacterial strains. The compounds showed antimicrobial activity against Gramnegative bacteria, which is due to N1–O bond activation. An introduction of alkyl groups on oxyacetic
acid moiety on N1 decreased the potency.
A series of 3-amino-β-lactam derivatives were synthesized and tested as potent anti-inammatory
agents.56 Various structural and stereochemical factors were required for N-Acylethanolamine Acid
Amidase (NAAA) inhibition. For this purpose, the inuence of size and shape of the C3 carbamic acid
ester side chain in addition to mono/disubstitution at C4 of β-lactam ring was investigated. The (S)conguration at C3, trans-vicinal position, length of aliphatic side chain, and lipophilic groups helped
to enhance the potency. But gem-dimethyl at C3 and oxygen atom in side chain had a detrimental effect.
This study identied a novel β-lactam derivative (IC50 0.085 ± 0.011 μM and >370-fold selectivity against
h-Ac) with NAAA inhibitory activity, improved stability, and drug-like prole.
Jarrahpour et al.57 reported the synthesis of mono- and bicyclic β-lactams via asymmetric cycloaddition. The asymmetric induction was performed by using chiral amino acid (D-phenylalanine ethyl
ester)-derived Schiff’s bases. These compounds were screened against a panel of Gram-positive and
69Monocyclic Beta-Lactams
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Gram-negative bacterial strains (B. subtilis, S. citrus, E. coli, K. pneumoniae). The results were compared with ampicillin and gentamycin. Some of the β-lactams (R3 =Bz, CH2OPh) demonstrated activity
against B. subtilis and S. citrus, while rest of the compounds were totally inactive against various strains.
Drazic et al.58 described the synthesis and biological evaluation of two new trans-(3R,4R)-aminoβ-lactams along with their diastereomeric mixtures as ezetimibe bioisosteres. These compounds were
screened for cytotoxicity and potential cholesterol absorption inhibitory activity. Importantly, in vitro
cholesterol absorption inhibition was observed in hNPC1L1/MDCKII cells. Moreover, these β-lactams
reduced cholesterol reduction in mice. The reduction caused by diastereomeric mixtures was found to be
comparable with that of ezetimibe.
Several β-lactam siderophore analogues were synthesized, and antimicrobial activities were evaluated
by McKee et al.59 Monocyclic (oxamazin) and bicyclic (carbacephalosporin) β-lactams were separately
linked to dihydroxy benzoyl derivatives of spermidine and lysine. These investigations were performed
to enhance the penetration of β-lactam antibiotics in bacterial cell wall using iron chelators (catechol
siderophore). A β-lactam showed antimicrobial activity against E. coli X580. The siderophore alone was
not active against E. coli X580. In addition, the potential of iron transport as a drug delivery system was
further elaborated in this study.
Dolence et al.60 incorporated N5-acetyl-N5-hydroxy-L-ornithyl-N5-acetyl-N5-hydroxy-L-ornithyl-N5acetyl-N5-hydroxy-L-ornithine as a carrier substructure into β-lactam antibiotics (carbacephalosporin
and oxamazin) to afford β-lactam conjugates. The antimicrobial evaluation of these conjugates was conducted. The potential as iron transport system in drug delivery was discussed. A β-lactam conjugate
displayed antimicrobial activity against Salmonella X514, but it was poorly active against other tested
Gram-positive and Gram-negative strains. In contrast, oxamazin analogues were found to be inactive.
Broccolo et al.61 carried out synthesis of 4-alkylidene-β-lactams and evaluated their antibacterial
activity against multi-drug-resistant bacterial strains. The designing of these compounds was done using
molecular modeling and QSAR-based studies. The active β-lactams showed excellent MIC values (0.25–
32 mg/L). It was found in the results that β-lactams with OMe and phenolic OH group showed better
activity, while carboxylic group resulted in decreased activity.
Cainelli et al.62 synthesized 4-alkylidene-β-lactam derivatives and investigated inhibitory activity
against leukocyte elastases and gelatinases (MMP-2 and MMP-9) using chromogenic substrates and
gelatine-zymographic assay methods. The SAR studies were conducted by varying different substituents
at N1, C3, and C4. The results showed that the presence of OH in place of OTBS lowered the potency
against LE. In addition, the absence of C3 substituent lowered the activity against LE but improved
the selective inhibition against MMP-2. Moreover, β-lactam with (E)-conguration at C4 gave better
potency in comparison to (Z)-conguration. Interestingly, N-acyl-β-lactams (IC50 4 μM) showed better
activity than N-acetyl and N-carbobenzyloxy against LE but were inactive against gelatinases. The C4
unsaturation on β-lactam was crucial for biological activity. The N-unsubstituted-β-lactam analogue
with OH substituent showed activity against MMP-9 (IC50 150 μM).
Following the previous study,63 a series of monocyclic 4-alkylidene-2-azetidinones anchored with
polyphenolic moieties were developed.59 The inuence of different substitutions on β-lactam ring towards
inhibition of HLE and matrix metalloproteases (MMP-2 and MMP-9) was investigated. It was found that
N-galloyl-β-lactam showed maximum activity (IC50 0.5 μM) against HLE, and N-benzoyl-β-lactam with
arylation on C3 hydroxy side chain had IC50 of 4 μM (Figure 2.16).
Harsha et al.64 synthesized monocyclic azetidin-2-one derivatives starting from anthranilic acid using
ketene-imine cycloaddition and screened for in vitro antibacterial and antifungal activity against S.
aureus, A. niger, and E. coli. The results were compared with gentamycin and uconazole as standard
compounds. β-Lactam having o-hydroxyphenyl at C4 resulted in moderate to very good antimicrobial
activ it y.
Iodination of 2-hydroxy-5-phenylbenzaldehyde and then treatment with aromatic amines afforded
Schiff’s bases. These on cyclocondensation with chloroacetyl chloride yielded a novel series of iodohydroxy biphenyl-substituted 2-azetidinones.65 All the new compounds were evaluated for antibacterial
activity against E. coli, X. citri, E. carotovora, and B. subtilis and were found to be active.
Chhajed et al.66 synthesized 8-hydroxylquinoline-substituted 3-chloro-β-lactams and evaluated them
for antilarial activity. The synthesized scaffolds were screened for in vitro antilarial activity against
70 Chemistry and Biology of Beta-Lactams
O
COOEt
O
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OTBS
O
N
O
H
O
OTBS COOEt
N
O
O O
FIGURE 2.16 4-Alkylidene-β-lactams.
OH
OEt
OH
OTBS
O
MeO
MeO
N
COOEt
OMe
OBn
O
O
OBn
OBn
COOBn
N
H
O
BnO
HO
OBn
COOEt
N
H
O
O
NH
O
B. malayi by measuring the percent loss of motility. The β-lactam having p-methoxyphenyl and methyl
groups at C4 resulted in 91% and 67% loss of motility, respectively, at a concentration of 60 mg/mL.
The observed activity was supported by molecular modeling studies carried out in the active site of
glutathione-S-transferase (GST) enzyme.
Subudhi and Ghosh67 synthesized several sulfanil amide-derived heterocyclic compounds including
β-lactams. Then, in vitro antibacterial evaluation against S. aureus, E. coli, E. faecalis, and P. aeruginosa was conducted, and results were compared with nitrofurantoin and ciprooxacin as positive con-
trols. β-Lactam demonstrated good antibacterial activity comparable to that of nitrofurantoin but very
less as compared to that of ciprooxacin.
A series of diversely substituted 4-[3- chlor o-4-s ubsti tuted pheny l-2-o xo-az etidi n-1-y l] benzoic acids
were prepared via cycloaddition by Pawar et al.68 These β-lactam derivatives were tested for in vivo
anticonvulsant activity using maximal electric shock (MES) method, and neurotoxicity study was also
carried out. The β-lactam having p-chlorophenyl and 4-hydroxyphenyl substituents exhibited anticonvulsant activity comparable to that standard drug (diazepam). Further, β-lactams having phenyl, cinnamyl, and 4-dimethylaminophenyl showed neurotoxicity.
Chimento et al.69 synthesized monocyclic 2-azetidinone derivatives as resveratrol analogues and
screened them for potential antiproliferative activity on human breast cancer cell line (MCF-7 and
SkBr3). One of the β-lactams displayed antitumor activity and better bioavailability than resveratrol
(Fig u re 2.17 ).
Veinberg et al.70 synthesized a series of 3,4-disubstituted and 1,3,4-trisubstituted β-lactams and studied
their in vitro anticancer activity against human brosarcoma and mouse hepatoma. The results showed
that compounds with 2-acetoxybenzoyloxymethyl and 2,2-dicyanovinyl at C4 of β-lactams demonstrated
best potency against various cancer cells in this series (Figure 2.18).
A series of 4-aminobenzoic acid-derived β-lactams were prepared by Sugumaran et al.71 The new
compounds were evaluated against S. aureus, E. coli, and C. albicans. The β-lactams with 4-dimethylaminophenyl and 4-hydroxyphenyl showed maximum antimicrobial activity against S. aureus and E.
coli. All these compounds were found to be less active than ciprooxacin and ketoconazole.
Gowri et al.72 conducted in silico and ex vivo studies on β-lactam against C. albicans to focus on the
mechanism of action. The MIC was signicantly improved when β-lactam was used with nystatin or
uconazole. The in silico studies demonstrated that the inhibition of ergosterol biosynthesis is due to
combining of the β-lactam in the active site of 14-α-demethylase. Further, it was observed that β-lactam
inhibits the growth of C. albicans via inhibition of cAMP pathway.
Synthesis and antimicrobial screening of monocyclic β-lactam were reported by Singh et al.73
The β-lactams were prepared by the treatment of 2-diazo-1,2-diarylethanone-generated ketene with
N-salicylideneamines. These compounds were tested in vitro against bacterial and fungal strains. The
β-lactam derivatives were found to be active against bacterial strains and showed similar results against
71Monocyclic Beta-Lactams
Cl
I
Cl
;
3C6
2
6
5
Br,
Cl;
Br,
Me
OCOMe
O
4-CH(Ph)
F
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HO
O
H H
N
2
R
N N
1
R
HO
9
R
N
O
Cl
N
O
N
OH
1
=
R
NO
NO
10
R
OMe
C
2
,
2
3-NO
Cl;
=
H
6
C
C
2
6
,
furfuryl;
4
8
=
R
H
4-ClC
,
5
6
H
-CH=CH-C
,
H
4
H, I,
4-NO
,
R
NO
6
4
H
4
C
2
6
=
H, I, Me,
,
COOH;
2
4-OMeC
,
H
;
FIGURE 2.17 3 - Chlor o -1,4-d iaryl- β-lactams.
HO
3
Cl
R
COOH
N
O
Cl
N
O
SO
2NH2
2
=
R
H
;
4
11
R
H
C
6
R
Cl;
9
=
R
CH
H
2-OHC
,
4
6
=
5
,
5
,
3
R
4-FC
=
H, I;
C
6
6
12
=
H
6
H
4-FC
,
5
H
,
4
10
R
4-BrC
,
4
6
R
3-NO
I
=
H,
H
6
2
Cl
O
COOH
H
6
NO
4-ClC
,
4
H
C
6
4
4
;
2
,
N
8
R
Cl
O
3
R
,
I,
H
6
4-NO
7
R
=
2-OHC
Cl,
,
4
2
4
R
R
6
R
N
6
R
Me;
4-OMeC
H
C
,
4
6
5
H
,
4
7
=
6
3,4,5-
11
R
12
R
4H,
H
4
Gram-positive and Gram-negative strains. In addition, β-lactam with p-chlorophenyl group at N1 and
p-methylphenyl groups at C3 demonstrated antibacterial and antifungal activity. These β-lactams were
more potent against C. mycoderma than S. cerevisiae.
O
N
O
HO
OMe
CN
N
PMP
O
1
=
R
4-ClC
4-OHC
H
,
4
6
H
6
4-CH
,
4-N(Me)
4
Ph,
2
C
2
6
FIGURE 2.18 Alkyl/arylated β-lactams.
Me
CN
CN
N
O
Me
O
OMe
F
2
R
2
R
O
2
=
H
R
;
4
2
N
R
H
C
6
OCOCH(R2)
3
4-CH
,
5
3C6
2
O
3
=
H
;
4
H
R
4-OMeC
C
,
5
6
1
R
N
COOH
OH
N
OH
H
,
4
6
4-MeC
H
,
4
6
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