Synthesis and biological evaluation of some new β-lactam-triazole hybrids

Article abstract of DOI:10.1007/s00044-015-1474-x

A series of novel β-lactams was synthesized from different imines and a special ketene derived from N-endo-5-norbornene-2,3-dicarboxyloylglycine 1 via the [2 + 2] ketene imine cycloaddition. Then, β-lactams 3a-h were treated with 1-azido-4-nitrobenzene 4

Full text of DOI:10.1007/s00044-015-1474-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1474-x
ORIGINAL RESEARCH
Synthesis and biological evaluation of some new b-lactam-triazole
hybrids
2
Aliasghar Jarrahpour1 Pouria Shirvani1 Veronique Sinou
•
•
•
´
Christine Latour2 Jean M. Brunel3
•
Received: 8 June 2015 / Accepted: 25 September 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of novel b-lactams was synthesized
from different imines and a special ketene derived from N-
Introduction
endo-5-norbornene-2,3-dicarboxyloylglycine
1
via the
The azetidine-2-one ring system is the key of biological
activities in b-lactam antibiotics which are a large group of
antibiotics, such as penicillins (Marchand-Brynaert and
[2 ? 2] ketene imine cycloaddition. Then, b-lactams 3a–
h were treated with 1-azido-4-nitrobenzene 4 to afford b-
lactam-triazole hybrids 5a–h. Of the twenty-three b-lac-
tams tested against chloroquine-resistant P. falciparum
K14 strain, 3a and 3d showed IC50 \ 20 lM, while 3j, 3m,
5a–5f exhibited IC50 \ 50. These newly synthesized b-
lactams were also tested against S. aureus, E. coli, P.
aeruginosa, C. albicans and C. glabrata and showed no
activity below 125 lg/mL.
´
Brule, 2008), cephalosporins (Alcaide et al., 2008),
nocardicins, carbapenems and monobactams (Palomo
et al., 2001; Alcaide et al., 2007; Deshmukh et al., 2004;
Halve et al., 2007), that have been widely used as
chemotherapeutic agents for treating microbial diseases
(Georg, 1993; Halve et al., 2007). In addition, it possess
many other pharmacological activities such as human
cytomegalovirus protease inhibitors (Borthwick et al.,
1998), LHRH antagonists (Guillon et al., 2007), cholesterol
absorption inhibitors (Burnett, 2004), anticancer agents
(Banik et al., 2010; O’Boyle et al., 2010), antihyper-
glycemic (Goel et al., 2004), antimalarial (Jarrahpour
et al., 2012), anti-HIV (Sperka et al., 2005), anti-inflam-
matory and analgesic activities (Saturnino et al., 2000).
Azoles are the widest group of antifungal drugs. They
are first-line drugs in the treatment of fungal infections,
because of their high therapeutic index. Besides their
antifungal activity (Rezaei et al., 2009), they show differ-
ent potential activities such as antibacterial (Bagihalli
et al., 2008), antitubercular (Wujec et al., 2008), antipro-
liferative (Manfredini et al., 2000), anti-HIV (Akhtar et al.,
2007) and antiviral (Holla et al., 2001).
Keywords b-Lactam Á
N-endo-5-norbornene-2,3-dicarboxyloylglycine Á
Triazole hybrids Á P. falciparum
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-015-1474-x) contains supplementary
material, which is available to authorized users.
& Aliasghar Jarrahpour
jarrah@susc.ac.ir
1
Department of Chemistry, College of Sciences, Shiraz
University, Shiraz 71454, Iran
However, the development of drug resistance for the
common antimicrobials has encouraged considerable
research efforts in the development of new drugs using
different approaches (Dondorp et al., 2009; Schlitzer,
2007) of which the molecular hybridization approach
(Meunier, 2007; Muregi and Ishih, 2010) is quite an
attractive strategy. Molecular hybridization is the logical
design of new chemical entities by the combination of two
2
ˆ
UMR-MD3 Relation hote-parasites, Physiopathologie &
´
Pharmacologie, Faculte de pharmacie, Aix-Marseille
Universite, Bd Jean Moulin, 13385 Marseille, France
´
3
´
Centre de Recherche en Cancerologie de Marseille (CRCM),
CNRS, UMR7258, Institut PaoliCalmettes, Inserm, U1068,
´
Faculte de Pharmacie, Aix-Marseille Universite, UM 105, 27
Bd Jean Moulin, 13385 Marseille Cedex 05, France
´
123

Med Chem Res
General procedure for the preparation of Schiff
bases 2a–q
distinct known bioactive pharmacophores into a single
molecule (Claudio et al., 2007; Walsh and Bell, 2009).
These two pharmacophores are usually picked out based on
their observed synergetic pharmacological activities. The
two most important profits of molecular hybridization are
increasing therapeutic efficacy and improving the
bioavailability profile (Claudio et al., 2007). Hybrid com-
pounds can be assembled by linking pharmacophore sub-
units directly or with spacer agents.
A mixture of aldehyde (9 mmol) and aromatic amine
(9 mmol) was refluxed in ethanol (20 mL) for 3–5 h. Then,
the solvent was evaporated under vacuum and crude oily
and solid Schiff bases were obtained. Crude solid Schiff
bases were filtered and washed with ethanol to afford pure
solid Schiff bases.
There are some reports of b-lactam-azole hybrid dis-
playing good antimicrobial activities (Kumar et al., 2012;
Raj et al., 2013; Vatmurge et al., 2008). Based on these
observations and in continuation of our interest for the syn-
thesis of new bioactive b-lactams, we report herein the
synthesis of some novel b-lactam-triazole hybrids and their
in vitro antibacterial, antifungal and antimalarial evaluation.
N-(4-chlorobenzylidene)-4-methoxyaniline
(2a) Light
silver crystal (yield 95 %, 2.1 g); mp: 121–123 °C; IR
(KBr, cm-1): 1620 (C=N) (Barbarotto et al., 2009).
N1-(2,3-dimethoxybenzylidene)-N4,N4-dimethylbenzene-
1,4-diamine (2b) Olive solid (yield 92 %, 2.3 g); mp:
229–230 °C; IR (KBr, cm-1): 1630 (C=N); 1H-NMR
(250 MHz, CDCl3) d (ppm): 2.97 (CH3, s, 6H), 3.80, 3.84
(2 OCH3, s, 6H), 6.72 (ArH, d, 2H, J = 8.62 Hz),
6.84–7.13 (ArH, m, 3H), 7.71 (ArH, d, 2H, J = 8.56 Hz),
7.96 (HC=N, s, 1H); 13C NMR (62.9 MHz, CDCl3) d
(ppm): 39.9 (CH3), 55.4, 55.6 (2OCH3), 110.5, 115.8,
116.9, 117.2, 118.5, 122.8, 138.4, 144.6, 147.3, 151.96
(aromatic carbons), 160.8 (C=N).
Experimental section
Materials
Chemical materials and solvents were obtained from
Merck, Fluka and Aldrich chemical companies. Solvents
were dried and purified by standard procedures. Melting
points were determined in open capillary tubes in Thermo
Fisher scientific IA9200 apparatus and are not corrected.
FTIR spectra were run on a Shimadzu FTIR-8300 spec-
trophotometer. NMR spectra were recorded on a Bruker
Avance DPX-250 (1H-NMR 250 MHz, 13C-NMR
62.9 MHz) spectrometer in CDCl3 or DMSO-d6 solvents
using TMS as an internal standard. Chemical shifts were
reported in ppm (d) downfield from TMS. All of the cou-
pling constants (J) are in Hertz. Mass spectra were obtained
on a Shimadzu GCMS-QP 1000 EX instrument at 70 eV.
The determination of the prepared products and reaction
monitoring were carried out on silica gel 254 analytical
sheets obtained from Fluka. Column chromatography was
carried out by silica gel 60 Merck (230-270).
N-(2-chlorobenzylidene)-2-(3,4-dimethoxyphenyl)ethanamine
(2c) Red oil (yield 93 %, 2.5 g); IR (KBr, cm-1): 1643
(C=N) (Weinbach and Hartung, 1950).
N-(2-chlorobenzylidene)-4-isopropylaniline (2d) Gray oil
(yield 94 %, 2.2 g); IR (KBr, cm-1): 1626 (C=N); 1H-NMR
(250 MHz, CDCl3) d (ppm): 1.14 (CH3, d, 6H, J = 6.95 Hz),
2.81 (CH, m, 1H), 7.07–7.29 (ArH, m, 8H), 8.12 (HC=N, s,
1H); 13C NMR (62.9 MHz, CDCl3) d (ppm): 18.8 (CH3), 26.5
(CH), 115.9, 121.8, 121.9, 123.3, 124.7, 126.7, 128.1, 130.7,
142.1, 144.2 (aromatic carbons), 150.96 (C=N).
N-(3,4-dimethoxybenzylidene)benzo[d][1,3]dioxol-5-amine
(2e) Brown solid (yield 96 %, 2.4 g); mp: 119.9–121 °C;
IR (KBr, cm-1): 1627 (C=N); 1H-NMR (250 MHz, CDCl3)
d (ppm): 3.87, 3.91 (2OCH3, 2 s, 6H), 5.91 (CH2, s, 2H),
6.73 (ArH, d, 2H, J = 7.83 Hz), 6.77 (ArH, d, 1H,
J = 8.41 Hz), 6.82 (ArH, s, 1H), 6.86 (ArH, s, 1H), 7.21
(ArH, dd, 1H, J = 8.36, J = 7.58 Hz), 8.27 (HC=N, s,
1H); 13C NMR (62.9 MHz, CDCl3) d (ppm): 56.0, 56.1
(2OCH3), 101.4 (CH2), 101.6, 108.3, 110.5, 115.1, 129.0,
129.8, 134.7, 137.0, 145.9, 148.3, 156.8 (aromatic car-
bons), 158.34 (C=N).
Synthesis of N-endo-5-norbornene-2,3-
dicarboxyloylglycine 1
To endo-5-norbornene-2,3-dicarboxylicanhydride (16.41 g,
100.0 mmol) dissolved in DMF (30 mL) was added glycine
(7.50 g, 100.0 mmol). The reaction mixture was refluxed for
24 h, cooled to room temperature, diluted with ethyl acetate
(70 mL) and washed with saturated aqueous ammonium
chloride solution (5 9 50 mL). The organic phase was dried
on anhydrous Na2SO4, filtered and evaporated in vacuo. The
residue was recrystallized (five times) from ethyl acetate
giving N-5-norbornene-2,3-dicarboxyloylglycine as a white
crystalline solid (yield 61 %, 13.5 g); mp: 149–151 °C.
N1-(4-isopropylbenzylidene)-N4,N4-dimethylbenzene-1,4-
diamine (2f) Yellow solid (yield 95 %, 2.3 g); mp:
99–100 °C; IR (KBr, cm-1): 1627 (C=N) (Gawinecki and
Muzalewski, 1984).
4-(((3,4-Dimethoxyphenethyl)imino)methyl)-N,N-dimethy-
laniline (2g) Yellow solid (yield 97 %, 2.7 g); mp:
123

Med Chem Res
1
114–116 °C; IR (KBr, cm-1): 1635 (C=N); 1H-NMR
(250 MHz, CDCl3) d (ppm): 2.94 (CH2–Ph, t, 2H,
J = 7.26 Hz), 3.00 (CH3, s, 6H), 3.75 (CH2–N, m, 2H),
3.79, 3.83 (2OCH3, s, 6H), 6.66 (ArH, d, 2H,
J = 7.42 Hz), 6.76 (ArH, s, 3H), 7.59 (ArH, d, 2H,
J = 8.05 Hz), 7.96 (HC=N, s, 1H); 13C NMR (62.9 MHz,
CDCl3) d (ppm): 37.2 (CH2–Ph), 40.2 (CH3), 55.7, 55.8
(2OCH3), 62.9 (CH2–N), 111.1, 111.6, 112.5, 120.8, 129.7,
132.7, 147.2, 148.5, -152.2 (aromatic carbons), 161.5
(C=N).
3322–3498 (OH); H-NMR (250 MHz, CDCl3) d (ppm):
2.60 (CH2–N, t, 4H), 3.74 (CH2, s, 2H), 3.74 (CH2–O, t,
4H), 5.94 (CH2–2O, s, 2H), 6.74–7.43 (ArH, m, 6H), 8.52
(HC=N, s, 1H), 13.61 (OH, brs, 1H); 13C NMR (62.9 MHz,
CDCl3) d (ppm): 53.5 (C-14), 56.4 (C-13), 66.8 (C-15),
101.5 (C-12), 101.7, 108.5, 115.4, 118.6, 119.2, 124.4,
131.2, 134.2, 142.8, 146.8, 148.5, 159.5 (aromatic car-
bons), 160.24 (C=N).
3-Methoxy-N-(3-methoxybenzylidene)aniline (2o) Black
oil (yield 91 %, 2.0 g); IR (KBr, cm-1): 1626 (C=N)
(Smith et al., 1988).
N-(3,4-dimethoxybenzylidene)-2,4-dimethoxyaniline (2h)
Green oil (yield 91 %, 2.4 g); IR (KBr, cm-1): 1632 (C=N)
(Adib et al., 2011).
N-(2,3-dimethoxybenzylidene)-4-isopropylaniline
(2p)
Red oil (yield 96 %, 2.4 g); IR (KBr, cm-1): 1689 (C=N);
1H-NMR (250 MHz, CDCl3) d (ppm): 1.15 (CH3, d, 6H,
J = 7.42), 2.79 (CH, m, 1H), 3.65, 3.72 (2OCH3, s, 6H),
6.85–7.12 (ArH, m, 3H), 7.32 (ArH, d, 2H, J = 7.85 Hz),
7.44 (ArH, d, 2H, J = 8.68 Hz), 8.52 (HC=N, s, 1H); 13C
NMR (62.9 MHz, CDCl3) d (ppm): 22.2 (CH3), 30.7 (CH),
57.3, 57.8 (2OCH3), 112.4, 114.8, 121.1, 122.5, 129.6,
143.2, 145.1, 153.2, 155.2 (aromatic carbons), 161.0
(C=N).
N-(anthracen-9-ylmethylene)benzo[d][1,3]dioxol-5-amine
(2i) Brown
solid
(yield
85 %,
2.5 g);
mp:
114.9–118.2 °C; IR (KBr, cm-1): 1620 (C=N); H-NMR
(250 MHz, CDCl3) d (ppm): 6.05 (CH2, s, 2H), 6.91–7.04
(ArH, m, 3H), 7.47–7.60 (ArH, m, 4H), 8.02 (ArH, d, 2H,
J = 6.95 Hz), 8.53 (ArH, s, 1H), 8.69 (ArH, d, 2H,
J = 9.16 Hz), 9.64 (HC=N, s, 1H); 13C NMR (62.9 MHz,
CDCl3) d (ppm): 101.5 (CH2), 102.0, 108.5, 114.9, 124.7,
125.4, 127.2, 129.0, 130.5, 131.3, 146.4, 147.1, 148.4
(aromatic carbons), 158.0 (C=N).
1
N1-(2,3-dimethoxybenzylidene)-N4,N4-diethylbenzene-1,4-
diamine (2q) Brown solid (yield 95 %, 2.7 g); mp:
96–98 °C; IR (KBr, cm-1): 1612 (C=N); 1H-NMR
N1-(4-(dimethylamino)benzylidene)-N4,N4-dimethylben-
zene-1,4-diamine (2j) Olive solid (yield 90 %, 2.2 g);
mp: 237.5–239 °C; IR (KBr, cm-1): 1633 (C=N) (Neu-
vonen et al., 2006).
(250 MHz, CDCl3)
d
(ppm): 1.13 (CH3, t, 6H,
J = 8.25 Hz), 3.52 (CH2, q, 4H), 3.64, 3.71 (2OCH3, s,
6H), 6.72–6.75 (ArH, d, 2H, J = 8.24 Hz), 6.92–7.21
(ArH, m, 3H), 7.38 (ArH, d, 2H, J = 7.37 Hz), 8.15
(HC=N, s, 1H); 13C NMR (62.9 MHz, CDCl3) d (ppm):
13.3 (CH3), 49.8 (CH2), 56.4, 57.1 (2OCH3), 114.4, 114.9,
115.8, 122.7, 124.1, 139.2, 141.4, 151.8, 154.3 (aromatic
carbons), 159.4 (C=N).
2-(3,4-Dimethoxyphenyl)-N-(4-isopropylbenzylidene) etha-
namine (2k) Red oil (yield 97 %, 2.7 g); IR (KBr, cm-1):
1
1643. (C=N); H-NMR (250 MHz, CDCl3) d (ppm): 1.16
(CH3, d, 6H, J = 7.04), 2.85 (CH, m, 1H), 3.10 (CH2–Ph, t,
2H, J = 8.25 Hz), 3.69 (CH2–N, m, 2H), 3.75, 3.87
(2OCH3, s, 6H), 6.62–6.67 (ArH, m, 3H), 7.43 (ArH, d, 2H,
J = 8.31 Hz), 7.54 (ArH, d, 2H, J = 7.98 Hz), 8.26
(HC=N, s, 1H); 13C NMR (62.9 MHz, CDCl3) d (ppm):
20.5 (CH3), 28.0 (CH), 35.0 (CH2–Ph), 55.1, 55.5
(2OCH3), 62.3 (CH2–N), 110.8, 111.1, 124.5, 127.1, 133.1,
133.9, 146.4, 148.3, 153.4 (aromatic carbons), 160.4
(C=N).
General procedure for the synthesis of monocyclic b-
lactams 3a–q
A mixture of Schiff base (7.0 mmol), triethylamine
(35.0 mmol),
N-5-norbornene-2,3-dicarboxyloylglycine
(10.5 mmol) and tosyl chloride (10.5 mmol) in dry CH2Cl2
(25 mL) was stirred at room temperature for 24 h. Then, it
was washed with HCl 1 N (30 mL), saturated NaHCO3
(30 mL) and brine (30 mL). The organic layer was dried on
anhydrous Na2SO4 and filtered, and the solvent was
evaporated to give crude product. It was filtered off and
purified by column chromatography.
N-(2,3-dimethoxybenzylidene)-2-(3,4
dimethoxyphenyl)
ethanamine (2l) Red oil (yield 89 %, 2.6 g); IR (KBr,
cm-1): 1638 (C=N) (Bian et al., 2006).
N-(4-chlorobenzylidene)-2-(3,4-dimethoxyphenyl)ethanamine
(2m) Orange solid (yield 90 %, 2.5 g); mp:
108.2–109.8 °C IR (KBr, cm-1): 1628 (C=N) (Tiwari
et al., 2006).
2-(2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-oxoazetidin-
3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-
dione (3a) White solid (yield 74 %, 2.3 g); mp:
264–267 °C. IR (KBr, cm-1): 1704 (CO imide), 1755 (CO
b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.47 (1H,
2-((Benzo[d][1,3]dioxol-4-ylimino)methyl)-6-(morpholi-
nomethyl) phenol (2n) Brown solid (yield 92 %, 2.8 g);
mp: 133.7–135 °C; IR (KBr, cm-1): 1610 (C=N),
123

Med Chem Res
d, J = 8.8 Hz, H-11), 1.68 (1H, d, J = 8.8 Hz, H-11),
3.27–3.30 (2H, m, H-6 and H-7), 3.35–3.37 (2H, m, H-5
and H-8), 3.67 (3H, s OCH3), 4.82 (1H, d, J = 2.52 Hz,
H-4), 4.99 (1H, d, J = 2.52 Hz, H-3), 6.11–6.21 (2H, 2m,
H-9 and H-10), 6.69 (2H, d, J = 8.95 Hz, ArH), 7.08–7.19
(4H, m, ArH), 7.26 (2H, d, J = 8.46 Hz, ArH); 13C NMR
(62.9 MHz, CDCl3) d (ppm): 45.3, 45.8 (C-5, C-10), 47.1,
47.9 (C-6, C-9), 52.1 (C-11), 55.4 (OCH3), 59.4 (C-4), 62.7
(C-3), 114.4, 118.9, 127.3, 129.6, 134.5, 134.8, 140.3,
144.6, 147.8, 148.2, 155.3 (C-9, C10 and aromatic car-
bons), 161.7 (CO, b-lactam), 177.0, 177.3 (CO, imide);
EIMS m/z = 450 [M?, 37Cl], 448 [M?, 35Cl]; Anal. Calcd
for C25H21ClN2O4: C, 66.89; H, 4.72; N, 6.24. Found: C,
66.95; H, 4.81; N, 6.30.
imide); MS m/z = 506 [M?]; Anal. Calcd for C28H27-
ClN2O5: C, 66.33; H, 5.37; N, 5.53. Found: C, 65.86; H,
5.48; N, 5.44.
2-(2-(2-Chlorophenyl)-1-(4-isopropylphenyl)-4-oxoazetidin-
3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-
dione (3d) White solid (yield 82 %, 2.6 g); mp:
200–202 °C; IR (KBr, cm-1): 1704 (CO imide) 1782 (CO
b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.17 (6H,
d, J = 6.69 Hz, H-13), 1.54 (1H, d, J = 8.34 Hz, H-11),
1.74 (1H, d, J = 8.34, Hz H-11), 2.84 (1H, m, H-12),
3.35–3.36 (2H, m, H-6 and H-7), 3.39–3.42 (2H, m, H-5
and H-8), 4.88 (1H, d, J = 2.52 Hz, H-4), 5.65 (1H, d,
J = 2.52 Hz, H-3), 6.18–6.26 (2H, 2m, H-9 and H-10),
7.14 (2H, d, J = 6.79 Hz, ArH), 7.21–7.43 (6H, m, ArH);
13C NMR (62.9 MHz, CDCl3) d (ppm): 23.9 (C-13), 33.6
(C-12), 45.0, 45.2 (C-6, C-7), 45.7, 46.0 (C-5, C-8), 52.2
(C-11), 56.3 (C-4), 62.0 (C-3), 117.4, 126.9, 127.1, 127.6,
129.7, 130.0, 132.4, 133.5, 134.6, 134.9, 145.2 (C-9, C10
and aromatic carbons), 161.2 (CO, b-lactam), 175.9, 176.3
(CO, imide); MS m/z = 461 [M?]; Anal. Calcd for C25-
H21ClN2O4: C, 70.35; H, 5.47; N, 6.08. Found: C, 69.97;
H, 5.68; N, 6.26.
2-(2-(2,3-Dimethoxyphenyl)-1-(4-(dimethylamino)phenyl)-
4-oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3b) Orange solid (yield 73 %,
2.5 g);mp: 191–193 °C; IR (KBr, cm-1): 1712 (CO imide),
1751 (CO b-lactam); 1H-NMR (250 MHz, CDCl3) d
(ppm): 1.51, 1.47 (1H, d, J = 8.8 Hz, H-11), 1.71 (1H, d,
J = 8.84 Hz, H-11), 2.84 (6H, s, NCH3), 3.30–3.31 (2H,
m, H-6 and H-7), 3.38–3.39 (2H, m, H-5 and H-8), 3.80,
3.85 (6H, 2 s, 2OCH3), 4.99 (1H, d, J = 2.52 Hz, H-4),
5.42 (1H, d, J = 2.52 Hz, H-3), 6.18–6.24 (2H, 2m, H-9
and H-10), 6.57 (2H, d, J = 8.68 Hz, ArH), 6.79–6.87 (2H,
m, ArH), 6.96 (1H, d, J = 7.89 Hz, ArH), 7.15 (2H, d,
J = 7.10 Hz, ArH); 13C NMR (62.9 MHz, CDCl3) d
(ppm): 40.8 (NCH3), 45.0, 45.2 (C-6, C-7), 46.7, 46.8 (C-5,
C-18), 52.0 (C-11), 54.9, 56.7 (2OCH3), 60.9 (C-4), 61.8
(C-3), 112.9, 118.5, 118.8, 124.6, 127.6, 129.4, 134.3,
134.8, 147.0, 147.7, 152.7 (C-9, C10 and aromatic car-
bons), 160.8 (CO, b-lactam), 176.2, 176.4 (CO, imide); MS
m/z = 487 [M?]; Anal. Calcd for C38H29N3O5: C, 68.98;
H, 6.00; N, 8.62. Found: C, 69.32; H, 5.67; N, 8.54.
2-(1-(Benzo[d][1,3]dioxol-5-yl)-2-(2,3-dimethoxyphenyl)-
4-oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3e) Cream solid (yield 78 %, 2.6 g);
mp: 178–180 °C; IR (KBr, cm-1): 1712 (CO imide) 1751
(CO b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.52
(1H, d, J = 8.85 Hz, H-11), 1.72 (1H, d, J = 8.85 Hz,
H-11), 3.31–3.33 (2H, m, H-6 and H-7), 3.38–3.42 (2H, m,
H-5 and H-8), 3.80, 3.86 (6H, 2 s, 2OCH3), 4.91 (1H, d,
J = 2.52 Hz, H-4), 4.96 (1H, d, J = 2.52 Hz, H-3), 5.88
(2H, q, J = 2.26 Hz, H-12), 6.15–6.27 (2H, 2m, H-9 and
H-10), 6.61 (2H, d, J = 2.68 Hz, ArH), 6.71 (1H, s, ArH),
6.82 (2H, s, ArH), 6.95 (2H, d, J = 1.26 Hz, ArH); 13C
NMR (62.9 MHz, CDCl3) d (ppm): 45.2, 45.2 (C-6, C-7),
45.7, 45.8 (C-5, C-18), 52.0 (C-11), 55.9, 56.0 (2OCH3),
60.3 (C-4), 62.8 (C-3), 100.0 (C-12), 101.2, 108.2, 110.4,
111.6, 118.9, 128.0, 131.8, 134.5, 134.7, 144.3, 147.8,
149.6, 149.8 (C-9, C10 and aromatic carbons), 161.2 (CO,
b-lactam), 176.2, 176.4 (CO, imide); MS m/z = 488 [M?];
Anal. Calcd for C27H24N2O7: C, 66.39; H, 4.95; N, 5.73.
Found: C, 65.74; H, 4.87; N, 6.07.
2-(2-(2-Chlorophenyl)-1-(3,4-dimethoxyphenethyl)-4-oxoaze-
tidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3
(2H)-dione (3c) White solid (yield 86 %, 3.0 g); mp:
197–199 °C; IR (KBr, cm-1): 1712 (CO imide), 1758 (CO
b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.34
(1H, d, J = 9.00 Hz, H-11), 1.49 (1H, d, J = 9.00 Hz,
H-11), 2.90 (2H, t, J = 7.58 Hz, H-13), 3.03–3.08 (2H, m,
H-6 and H-7), 3.19–3.23 (2H, m, H-5 and H-8), 3.32, 4,03
(2H, 2m, H-12), 3.80, 3.86 (6H, 2 s, 2OCH3), 4.93 (1H, d,
J = 5.21 Hz, H-4), 5.22 (1H, d, J = 5.21 Hz, H-3),
6.69–6.80 (2H, 2m, H-9 and H-10), 7.25–7.42 (7H, m,
ArH); 13C NMR (62.9 MHz, CDCl3) d(ppm): 30.2 (C-13),
42.6 (C-12), 44.5, 44.8 (C-6, C-7), 45.3, 45,9 (C-5, C-18),
51.2 (C-11), 55.8, 55.9 (2OCH3), 58.8 (C-4), 59.4 (C-3),
111.3, 111.4, 120.5, 128.6, 129.2, 129.6, 129.7, 130.2,
131.4, 133.4, 133.7, 147.8 -149.0 (C-9, C10 and aromatic
carbons 164.25 (CO, b-lactam), 175.71, 175.79 (CO,
2-(1-(4-(Dimethylamino)phenyl)-2-(4-isopropylphenyl)-4-
oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3f) Yellow solid (yield 62 %, 2.0 g);
mp: 268–269 °C; IR (KBr, cm-1): 1712 (CO imide), 1743
(CO b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.21
(6H, d, J = 6.79 Hz, H-13), 1.53 (1H, d, J = 9.00 Hz,
H-11), 1.73 (1H, d, J = 9.00 Hz, H-11), 2.87 (7H, s, H-12
and NCH3), 3.30–3.33 (2H, m, H-6 and H-7), 3.40–3.43
123

Med Chem Res
(2H, m, H-5 and H-8), 4.91 (1H, d, J = 2.52 Hz, H-4),
5.05 (1H, d, J = 2.52 Hz, H-3), 6.18–6.29 (2H, 2m, H-9
and H-10), 6.64 (2H, d, J = 9.00 Hz, ArH), 7.18 (6H, q,
J = 3.00 Hz, ArH); 13C NMR (62.9 MHz, CDCl3) d
(ppm): 23.8 (C-13), 33.8 (C-12), 40.8 (NCH3), 45.2 (C-6,
C-7), 45.7 (C-5, C-8), 52.0 (C-11), 59.8 (C-4), 62.7 (C-3),
112.9, 119.0, 125.9, 127.3, 133.4, 134.5, 134.7, 147.7,
149.5 (C-9, C10 and aromatic carbons), 160.7 (CO, b-
lactam), 176.2, 176.5 (CO, imide); MS m/z = 469 [M?];
Anal. Calcd for C29H31N3O3: C, 74.18; H, 6.65; N, 8.95.
Found: C, 73.97; H, 5.88; N, 9.13.
2-(2-(Anthracen-9-yl)-1-(benzo[d][1,3]dioxol-5-yl)-4-oxoaze-
tidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3
(2H)-dione (3i) Green solid (yield 64 %, 2.4 g); mp:
257–259 °C; IR (KBr, cm-1): 1712 (CO imide), 1751 (CO
1
b-lactam); H-NMR 250 MHz (DMSO-d6) d (ppm): 1.54
(1H, d, J = 6.9 Hz, H-11), 1.73 (1H, d, J = 6.9 Hz, H-11),
3.30–3.38 (2H, m, H-6 and H-7), 3.46–3.50 (2H, m, H-5
and H-8), 5.68 (1H, d, J = 2.84 Hz, H-4), 5.78 (3H, m,
H-3 and H-12), 5.88–5.96 (2H, 2m, H-9 and H-10),
6.38–6.50 (2H, m, ArH), 6.77 (1H, d, J = 3.15 Hz, ArH),
7.44–7.55 (4H, m, ArH), 8.03 (2H, d, J = 8.68 Hz, ArH),
8.31 (2H, d, J = 8.53 Hz, ArH), 8.51 (1H, s, ArH); 13C
NMR (62.9 MHz, DMSO-d6) d (ppm): 44.4, 45.1, (C-6,
C-7), 45.3, 45.9 (C-5, C-8), 51.6 (C-11), 55.9 (C-4), 61.0
(C-3), 99.4 (C-12), 108.3, 109.7, 123.1, 125.1, 126.9,
127.3, 128.5, 129.4, 129.6, 130.4, 131.5, 134.7, 134.8,
144.5, 148.0 (C-9, C10 and aromatic carbons), 160.9 (CO,
b-lactam), 174.9, 175.7 (CO, imide); MS m/z = 528 [M?];
Anal. Calcd for C33H24N2O5: C, 74.99; H, 4.58; N, 5.30.
Found: C, 74.02; H, 3.98; N, 5.60.
2-(1-(3,4-Dimethoxyphenethyl)-2-(4-(dimethylamino)phenyl)-
4-oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3g) Orange solid (yield 71 %, 2.5 g);
mp: 145–146 °C; IR (KBr, cm-1): 1697 (CO imide), 1751
(CO b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm):
1.62 (1H, d, J = 9.16 Hz, H-11), 1.72 (1H, d,
J = 9.16 Hz, H-11), 2.87 (2H, m, H-13), 2.95 (6H, s,
NCH3), 3.06, 3,68 (2H, 2m, H-12), 3.28–3.30 (2H, m,
H-6 and H-7), 3.33–3.42 (2H, m, H-5 and H-8), 3.80, 3.86
(6H, 2 s, 2OCH3), 4.42 (1H, d, J = 2.36 Hz, H-4), 4.76
(1H, d, J = 2.36 Hz, H-3), 6.10–6.21 (2H, 2m, H-9 and
H-10), 6.64–6.77 (5H, m, ArH), 6.88 (2H, d,
J = 8.68 Hz, ArH); 13C NMR (62.9 MHz, CDCl3) d
(ppm): 30.6 (C-13), 40.4 (NCH3), 42.0 (C-12), 45.1, 45.2
(C-6, C-7), 45.7 (C-5, C-18), 51.9 (C-11), 56.7, 56.9
(2OCH3), 60.9 (C-4), 62.4 (C-3), 111.1, 112.0, 112.5,
120.7, 127.5, 131.2, 134.3, 134.7, 147.5, 148.7, 150.8 (C-
9, C10 and aromatic carbons), 164.4 (CO, b-lactam),
176.2, 176.5 (CO, imide); MS m/z = 515 [M?]; Anal.
Calcd for C30H33N3O5: C, 69.88; H, 6.45; N, 8.15. Found:
C, 69.62; H, 6.32; N, 8.36.
2-(1,2-Bis(4-(dimethylamino)phenyl)-4-oxoazetidin-3-yl)-
3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-
dione (3j) Brownish solid (yield 65 %, 2.1 g); mp:
263.4–263.8 °C; IR (KBr, cm-1): 1712 (CO imide), 1743
(CO b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.46
(1H, d, J = 8.37 Hz, H-11), 1.66 (1H, d, J = 8.37 Hz,
H-11), 2.78, 2.86 (12H, 2 s, NCH3), 3.23–3.25 (2H, m, H-6
and H-7), 3.32–3.35 (2H, m, H-5 and H-8), 4.83 (1H, d,
J = 2.84 Hz, H-4), 5.91 (1H, d, J = 2.84 Hz, H-3),
6.09–6.20 (2H, 2m, H-9 and H-10), 6.50 (2H, d,
J = 8.53 Hz, ArH), 6.57 (2H, d, J = 8.53 Hz, ArH),
7.03–7.19 (4H, m, ArH); 13C NMR (62.9 MHz, CDCl3) d
(ppm): 39.4, 39.8 (NCH3), 44.1, 44.2 (C-6, C-7), 44.7, 44.8
(C-5, C-8), 50.9 (C-11), 58.9 (C-4), 61.7 (C-3), 111.7,
112.0, 118.0, 122.0, 126.0, 130.6, 132.2, 133.4, 133.7, (C-
9, C10 and aromatic carbons), 160.0 (CO, b-lactam), 175.2,
175.4 (CO, imide); MS m/z = 470 [M?]; Anal. Calcd for
C28H3N4O3: C, 71.47; H, 6.43; N, 11.91. Found: C, 72.97;
H, 6.74; N, 11.43.
2-(1-(2,4-Dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)-4-
oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3h) Golden solid (yield 45 %,
1.6 g); mp: 267–268.5 °C; IR (KBr, cm-1): 1704 (CO
1
imide), 1743 (CO b-lactam); H-NMR (250 MHz, CDCl3)
d1.54 (2H, t, J = 9.16 Hz, H-11), 3.28–3.35 (2H, m, H-6
and H-7,), 3.42–3.44 (2H, m, H-5 and H-8), 3.66, 3.68
(12H, 2 s, 4OCH3), 4.78 (1H, d, J = 2.52 Hz, H-4), 5.20
(1H, d, J = 2.52 Hz, H-3), 5.97–6.26 (2H, 2m, H-9 and
H-10), 6.46–7.35 (6H, m, ArH); 13C NMR (62.9 MHz,
DMSO-d6) d (ppm): 44.5, 44.6 (C-6, C-7), 45.2, 45.7 (C-5,
C-8), 52.4 (C-11), 55.5, 55.9, 56.3, 56.4 (4OCH3), 60.4 (C-
4), 62.9 (C-3), 100.0, 101.2, 108.2, 110.4, 111.6, 118.9,
131.8, 134.7, 144.3, 147.8, 149.6, 149.8 (C-9, C10 and
aromatic carbons), 161.2 (CO, b-lactam), 176.7, 176.9
(CO, imide); MS m/z = 504 [M?, 37Cl], 448 [M?, 35Cl];
Anal. Calcd for C28H28N2O7: C, 66.66; H, 5.59; N, 5.55.
Found: C, 66.51; H, 5.36; N, 5.75.
2-(1-(3,4-Dimethoxyphenethyl)-2-(4-isopropylphenyl)-4-
oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3k) Yellow solid (yield 67 %,
2.4 g); mp: 165–168 °C; IR (KBr, cm-1): 1704 (CO
1
imide), 1758 (CO b-lactam); H-NMR (250 MHz, CDCl3)
d (ppm): 1.22, (6H, s, H-15), 1.52 (1H, d, J = 8.88 Hz,
H-11), 1.72 (1H, d, J = 8.88 Hz, H-11), 2.81–2.93 (3H, m,
H-13 and H-14), 3.06, 3,70 (2H, 2m, H-12), 3.26–3.31 (2H,
m, H-6 and H-7), 3.37–3.42 (2H, m, H-5 and H-8), 3.78,
3.86 (6H, 2 s, 2OCH3), 4.44 (1H, d, J = 2.36 Hz, H-4),
4.75 (1H, d, J = 2.36 Hz, H-3), 6.12–6.20 (2H, 2m, H-9
123

Med Chem Res
and H-10), 6.66–7.27 (7H, m, ArH); 13C NMR (62.9 MHz,
CDCl3) d (ppm): 23.9 (C-15), 30.5 (C-13), 30.8 (C-14),
42.2 (C-12), 45.1, 45.2 (C-6, C-7), 46.7 (C-5, C-18), 52.0
(C-11), 55.7, 55.9 (2OCH3), 59.9 (C-4), 62.5 (C-3), 111.1,
111.9, 120.7, 126.4, 127.1, 131.1, 132.8, 134.4, 134.7,
147.6, 148,8, 149.7 (C-9, C10 and aromatic carbons), 164.3
(CO, b-lactam), 176.2, 176.5 (CO, imide); MS m/z = 514
[M?]; Anal. Calcd for C31H34N2O5: C, 72.35; H, 6.66; N,
5.44. Found: C, 72.54; H, 6.87; N, 4.93.
1H-4,7-methanoisoindole-1,3(2H)-dione (3n) Orange
solid (yield 59 %, 2.2 g); mp: 250–251.6 °C; IR (KBr,
cm-1): 1704 (CO imide), 1758.9 (CO b-lactam),
1
3260–3540.9 (OH); H-NMR (250 MHz, CDCl3) d (ppm):
1.53 (1H, d, J = 8.53 Hz, H-11), 1.73 (1H, d,
J = 8.53 Hz, H-11), 2.55(4H, s, H-14) 3.33–3.36 (2H, m,
H-6 and H-7), 3.41–3.447 (2H, m, H-5 and H-8), 3.67 (2H,
s, H-13), 3.77 (4H, t, J = 4.26 Hz, H-15), 4.99 (1H, d,
J = 2.36 Hz, H-4), 5.39 (1H, d, J = 2.36 Hz, H-3), 5.89
(2H, d, J = 2.21 Hz, H-12), 6.16–6.29 (2H, 2m, H-9 and
H-10), 6.64–7.27 (6H, m, ArH), 10.20 (brds, 1H, OH); 13
C
2-(1-(3,4-Dimethoxyphenethyl)-2-(2,3-dimethoxyphenyl)-4-
oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3l) Yellow solid (yield 86 %, 3.2 g);
mp: 90.1–91 °C; IR (KBr, cm-1): 1712 (CO imide), 1758
(CO b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.34
(1H, d, J = 8.21 Hz, H-11), 1.49 (1H, d, J = 8.21 Hz,
H-11), 2.83–2.91 (2H, m, H-13), 3.02–3.11 (2H, m, H-6
and H-7), 3.18–3.22 (2H, m, H-5 and H-8), 3.33, 3,96 (2H,
2m, H-12), 3.71, 3.80, 3.84 (12H, 3 s, 4OCH3), 4.97 (1H,
d, J = 5.37 Hz, H-4), 5.13 (1H, d, J = 5.37 Hz, H-3),
6.11–6.31 (2H, 2m, H-9 and H-10), 6.69–7.05 (6H, m,
ArH); 13C NMR (62.9 MHz, CDCl3) d (ppm): 33.2 (C-13),
42.3 (C-12), 44.6, 44.7 (C-6, C-7), 45.4, 45,8 (C-5, C-18),
51.9 (C-11), 55.7, 55.7, 55.8, 55.9 (4OCH3), 59.2 (C-4),
60.4 (C-3), 111.3, 111.4, 112.3, 120.4, 123.3, 126.9, 130.5,
133.5, 133.7, 134.6, 147.7, 149.0, 152.4 (C-9, C10 and
aromatic carbons), 164.2 (CO, b-lactam), 175.8, 176.0
(CO, imide); MS m/z = 532 [M?]; Anal. Calcd for C30-
H32ClN2O7: C, 67.66; H, 6.06; N, 5.26. Found: C, 68.12;
H, 5.68; N, 5.13.
NMR (62.9 MHz, CDCl3) d (ppm): 46.7, 46.8 (C-6, C-7),
46.9 (C-5, C-18), 51.8 (C-11), 53.1 (C-14), 55.8 (C-13),
59.9 (C-4), 62.2 (C-3), 99.9 (C-12), 101.3, 108.3, 110.4,
110.7, 110.8, 116.9, 121.0, 124.4, 128.8, 129.2, 146.0,
147.4, 149.5 (C-9, C10 and aromatic carbons), 162.2 (CO,
b-lactam), 176.2, 176.6 (CO, imide); MS m/z = 543 [M?];
Anal. Calcd for C30H29N3O7: C, 66.29; H, 5.38; N, 7.73.
Found: C, 67.04; H, 4.92; N, 7.12.
2-(1,2-Bis(3-methoxyphenyl)-4-oxoazetidin-3-yl)-3a,4,7,7a-
tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione (3o) Yel-
low solid (yield 57 %, 1.8 g); mp: 267–-268.5 °C; IR
1
(KBr, cm-1): 1704 (CO imide), 1758 (CO b-lactam); H-
NMR (250 MHz, CDCl3) d(ppm): 1.52 (1H, d,
J = 7.74 Hz, H-11), 1.72 (1H, d, J = 7.74 Hz, H-11),
3.31–3.34 (2H, m, H-6 and H-7), 3.36–3.43 (2H, m, H-5
and H-8), 3.71, 3.75 (6H, 2 s, 2OCH3), 4.94 (1H, d,
J = 2.52 Hz, H-4), 5.06 (1H, d, J = 2.52 Hz, H-3),
5.18–6.28 (2H, 2m, H-9 and H-10), 6.57–7.30 (8H, m,
ArH); 13C NMR (62.9 MHz, CDCl3) d (ppm): 45.2, 45.3
(C-6, C-7), 46.7 (C-5, C-8), 52.0 (C-11), 55.2 (2OCH3),
59.9 (C-4), 62.6 (C-3), 103.3, 108.6, 109.6, 110.4, 111.6,
114.1, 118.1, 129.8, 130.5, 134.5, 134.7, 138.2, 160.0,
160.3 (C-9, C10 and aromatic carbons), 161.5 (CO, b-
lactam), 176.2, 176.4 (CO, imide); MS m/z = 444 [M?,
37Cl]; Anal. Calcd for C26H24N2O5: C, 70.26; H, 5.44; N,
6.30. Found: C, 69.66; H, 5.12; N, 7.18.
2-(2-(4-Chlorophenyl)-1-(3,4-dimethoxyphenethyl)-4-oxoaze-
tidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3
(2H)-dione (3m) White solid (yield 84 %, 3.0 g); mp:
160.5–162 °C; IR (KBr, cm-1): 1712 (CO imide), 1758
(CO b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.53
(1H, d, J = 8.68 Hz, H-11), 1.74 (1H, d, J = 8.68 Hz,
H-11), 2.80–2.92 (2H, m, H-13), 3.09, 3,73 (2H, 2m,
H-12), 3.30–3.32 (2H, m, H-6 and H-7), 3.38–3.43 (2H, m,
H-5 and H-8), 3.80, 3.86 (6H, 2 s, 2OCH3), 4.42 (1H, d,
J = 2.36 Hz, H-4), 4.71 (1H, d, J = 2.36 Hz, H-3),
6.10–6.20 (2H, 2m, H-9 and H-10), 6.64–6.73 (3H, m,
ArH), 6.90 (2H, d, J = 8.53 Hz, ArH), 7.27 (2H, d,
J = 8.53 Hz, ArH); 13C NMR (62.9 MHz, CDCl3) d
(ppm): 33.6 (C-13), 42.3 (C-12), 45.2 (C-6, C-7), 45.7 (C-
5, C-18), 52.0 (C-11), 55.7, 55.9 (2OCH3), 59.5 (C-4), 62.5
(C-3), 111.2, 112.0, 120.6, 127.8, 129.2, 130.9, 134.2,
134.4, 134.7, 134.8, 147.6, 148.8 (C-9, C10 and aromatic
carbons), 164.0 (CO, b-lactam), 176.1, 176.4 (CO, imide);
MS m/z = 506 [M?]; Anal. Calcd for C28H27ClN2O5: C,
66.33; H, 5.37; N, 5.53. Found: C, 67.07; H, 5.12; N, 5.28.
2-(2-(3,4-Dimethoxyphenyl)-1-(4-isopropylphenyl)-4-oxoaze-
tidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3
(2H)-dione (3p) White solid (yield 88 %, 3.0 g); mp:
189–190.8 °C; IR (KBr, cm-1): 1704 (CO imide), 1766
(CO b-lactam); 1H-NMR (250 MHz, CDCl3) d (ppm): 1.15
(6H, d, J = 6.95, H-13), 1.52 (1H, d, J = 8.84 Hz, H-11),
1.72 (1H, d, J = 8.84 Hz, H-11), 2.78–2.87 (1H, m, H-12),
3.28–3.33 (2H, m, H-6 and H-7), 3.36–3.44 (2H, m, H-5
and H-8), 3.81, 3.87 (6H, 2 s, 2OCH3), 5.02 (1H, d,
J = 2.36 Hz, H-4), 5.44 (1H, d, J = 2.36 Hz, H-3),
6.18–6.27 (2H, 2m, H-9 and H-10), 6.81–7.22 (7H, m,
ArH); 13C NMR (62.9 MHz, CDCl3) d (ppm): 23.9 (C-13),
30.6 (C-12), 45.1, 45.2 (C-6, C-7), 46.7 (C-5, C-18), 52.0
(C-11), 55.0, 55.7 (2OCH3), 60.9 (C-4), 61.9 (C-3), 112.7,
2-(1-(Benzo[d][1,3]dioxol-5-yl)-2-(2-hydroxy-3-(morpholi-
nomethyl)phenyl)-4-oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-
123

Med Chem Res
117.3, 118.4, 124.7, 126.9, 129.2, 134.3, 134.8, 135.0,
144.8, 148.9, 152.75 (C-9, C10 and aromatic carbons),
161.5 (CO, b-lactam), 176.1, 176.4 (CO, imide); MS m/
z = 486 [M?]; Anal. Calcd for C29H30N2O5: C, 71.59; H,
6.21; N, 5.76. Found: C, 70.89; H, 6.45; N, 5.39.
C, 60.74; H, 4.11; N, 13.71. Found: C, 61.22; H, 4.41; N,
13.48.
6-(2-(2,3-Dimethoxyphenyl)-1-(4-(dimethylamino)phenyl)-
4-oxoazetidin-3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahy-
dro-4,8-methano[1,2,3]triazolo[4,5-f]isoindole-5,7(3aH,6H)-
dione (5b) Golden solid (yield 78 %, 0.5 g); mp: 228 °C
decomposed; IR (KBr, cm-1): 1596 (N=N), 1712 (CO
2-(1-(4-(Diethylamino)phenyl)-2-(2,3-dimethoxyphenyl)-4-
oxoazetidin-3-yl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoin-
dole-1,3(2H)-dione (3q) Brown oil (yield 90 %, 3.2 g);
IR (KBr, cm-1): 1712 (CO imide), 1751 (CO b-lactam);
1H-NMR (250 MHz, CDCl3) d (ppm): 1.10 (6H, t,
J = 3.47 Hz, H-13), 1.36 (1H, d, J = 7.58 Hz, H-11), 1.52
(1H, d, J = 7.58 Hz, H-11), 3.05–3.13 (2H, m, H-6 and
H-7), 3.23–3.39 (6H, m, H-5, H-8 and H-12), 3.85, 3.87
(6H, 2 s, 2OCH3), 5.37 (1H, d, J = 3.47 Hz, H-4), 5.52
(1H, d, J = 3.47 Hz, H-3), 6.56–6.61 (2H, 2m, H-9 and
H-10), 6.87–7.30 (7H, m, ArH); 13C NMR (62.9 MHz,
CDCl3) d (ppm): 12.4 (C-13), 44.3 (C-12), 44.5, 44.7 (C-6,
C-7), 45.4 (C-5, C-18), 51.8 (C-11), 55.6, 56.3 (2OCH3),
58.3 (C-4), 60.4 (C-3), 112.0, 112.2, 118.5, 121.2, 123.2,
126.1, 126.7, 133.8, 144.7, 147.2, 152.1 (C-9, C10 and
aromatic carbons), 160.3 (CO, b-lactam), 175.7, 175.9
(CO, imide); MS m/z = 515 [M?].
1
imide), 1751 (CO b-lactam); H-NMR (250 MHz, CDCl3)
d (ppm): 1.36 (1H, d, J = 11.05 Hz, H-11), 1.59 (1H, d,
J = 11.05 Hz, H-11), 2.89 (6H, s, NCH3), 3.10–3.19 (2H,
m, H-5 and H-8), 3.31–3.40 (2H, m, H-6 and H-7), 3.67,
3.76 (6H, 2 s, OCH3), 4.01, 4.85 (2H, 2d, J = 9.04 Hz,
H-9 and H-10), 5.10 (1H, d, J = 2.68 Hz, H-4), 5.61 (1H,
d, J = 2.68 Hz, H-3), 6.62 (2H, d, J = 7.10 Hz, ArH),
6.81–7.22 (5H, m, ArH), 7.36 (2H, t, J = 9.63 Hz, ArH),
8.23 (2H, m, ArH); 13C NMR (62.9 MHz, CDCl3) d (ppm):
35.6 (C-11), 40.7 (NCH3), 42.6, 43.7 (C-5, C-8), 45.4, 45.6
(C-6, C-7), 55.1 (C-9), 54.8, 56.7 (2OCH3), 60.8 (C-4),
62.0 (C-3), 83.2 (C-10), 112.9, 113.4, 113.6, 118.2, 118.9,
124.7, 126.0, 127.1, 128.8, 142.4, 144.4, 146.6, 148.0,
152.6 (aromatic carbons), 160.2 (CO, b-lactam), 174.6,
175.1 (CO, imide); Anal. Calcd for C34H33N7O7: C, 62.66;
H, 5.10; N, 15.05. Found: C, 62.31; H, 4.66; N, 14.77.
General procedure for the synthesis of b-lactam-
triazole hybrids 5a–h
6-(2-(2-Chlorophenyl)-1-(3,4-dimethoxyphenethyl)-4-oxoaze-
tidin-3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahydro-4,8
methano [1,2,3] triazolo[4,5-f]isoindole-5,7(3aH,6H)-
dione (5c) Brown solid (yield 71 %, 0.5 g); mp: 225 °C
decomposed; IR (KBr, cm-1): 1596 (N=N), 1712 (CO
A mixture of p-nitrophenyl azide (1 mmol) and an appro-
priate b-lactam 3a–h (1 mmol) in 10–15 mL of anhydrous
toluene was refluxed till the completion of the reaction
(TLC monitoring). The solvent was removed under
reduced pressure, and the precipitate was filtered off,
washed with toluene and dried in air.
1
imide), 1766 (CO b-lactam); H-NMR (250 MHz, CDCl3)
d (ppm): 1.10 (1H, d, J = 10.58 Hz, H-11), 1.40 (1H, d,
J = 10.58 Hz, H-11), 2.90–2.96 (2H, m, H-13), 2.97–3.23
(4H, m, H-5, H-8, H-6 and H-7), 3.80, 3.85 (6H, 2 s,
2OCH3), 3.38, 4.07 (2H, 2m, H-12), 4.26, 4.76 (2H, 2d,
J = 9.79 Hz, H-9 and H-10), 5.01 (1H, d, J = 2.68 Hz,
H-4), 5.41 (1H, d, J = 2.68 Hz, H-3), 6.62–7.49 (9H, m,
ArH), 8.25 (2H, dt, J = 9.47, J = 3.15 Hz, ArH); 13C
NMR (62.9 MHz, CDCl3) d (ppm): 33.2 (C-11), 35.2 (C-
13), 41.7, 42.8 (C-5, C-8), 43.7 (C-12), 44.8, 45.0 (C-6,
C-7), 54.9 (C-9), 56.7 (2OCH3), 56.9 (C-4), 59.3 (C-3),
82.8 (C-10), 111.4, 113.3, 120.5, 125.8, 126.1, 127.2,
129.0, 129.5, 129.8, 130.0, 130.5, 131.1, 131.6, 143.7,
144.2, 149.1 (aromatic carbons), 163.4 (CO, b-lactam),
173.8, 174.2 (CO, imide); Anal. Calcd for C34H31ClN6O7:
C, 60.85; H, 4.66; N, 12.52. Found: C, 61.41; H, 4.38; N,
12.16.
6-(2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-oxoazetidin-
3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahydro-4,8-methano
[1,2,3]triazolo[4,5-f]isoindole-5,7(3aH,6H)-dione (5a) Olive
solid (yield 74 %, 0.4 g); mp: 275 °C decomposed; IR
(KBr, cm-1): 1589 (N=N), 1712 (CO imide), 1758 (CO b-
lactam); 1H-NMR (250 MHz, CDCl3) d 1.18 (1H, d,
J = 10.26 Hz, H-11), 1.86 (1H, d, J = 10.26 Hz, H-11),
3.09–3.15 (2H, m, H-5 and H-8), 3.20–3.24 (2H, m, H-6
and H-7), 3.66 (3H, s, OCH3), 3.84, 4.79 (2H, 2d,
J = 8.68 Hz, H-9 and H-10), 4.91 (1H, d, J = 2.52 Hz,
H-4), 5.11 (1H, d, J = 2.52 Hz, H-3), 6.66 (2H, d,
J = 9.00 Hz, ArH), 6.90 (2H, d, J = 9.79 Hz, ArH),
7.01–7.21 (6H, m, ArH), 8.03 (2H, d, J = 8.37 Hz, ArH);
13C NMR (62.9 MHz, CDCl3) d (ppm): 32.0 (C-11), 37.1,
37.9 (C-5, C-8), 47.1, 47.5 (C-6, C-7), 53.4 (C-9), 55.4
(OCH3), 59.0 (C-4), 62.9 (C-3), 82.6 (C-10), 114.4, 118.9,
120.7, 125.3, 127.3, 129.7, 130.0, 1340, 135.1, 142.6,
156.7, 157.6 (aromatic carbons), 160.4 (CO, b-lactam),
175.3, 176.0 (CO, imide); Anal. Calcd for C31H25ClN6O6:
6-(2-(2-Chlorophenyl)-1-(4-isopropylphenyl)-4-oxoazetidin-
3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahydro-4,8-methano
[1,2,3]triazolo[4,5-f]isoindole-5,7(3aH,6H)-dione (5d) Olive
solid (yield 78 %, 0.5 g); mp: 175 °C decomposed; IR
(KBr, cm-1): 1596 (N=N), 1712 (CO imide), 1766 (CO b-
1
lactam); H-NMR (250 MHz, CDCl3) d (ppm): 1.20 (6H,
123

Med Chem Res
d, J = 6.16 Hz, H-13), 1.37 (1H, d, J = 11.21 Hz, H-11),
1.60 (1H, d, J = 11.21 Hz, H-11), 2.89 (1H, m, H-12),
3.14–3.21 (2H, m, H-5 and H-8), 3.34–3.43 (2H, m, H-6
and H-7), 3.97, 4.84 (2H, 2d, J = 8.68 Hz, H-9 and H-10),
5.06 (1H, d, J = 2.68 Hz, H-4), 5.84 (1H, d, J = 2.68 Hz,
H-3), 7.13–7.42 (10H, m, ArH), 8.20 (2H, d, J = 9.47 Hz,
ArH); 13C NMR (62.9 MHz, CDCl3) d (ppm): 23.9 (C-13),
33.6 (C-11), 35.7 (C-12), 42.8, 43.6 (C-5, C-8), 45.5, 45.6
(C-6, C-7), 55.2 (C-9), 56.3 (C-4), 62.1 (C-3), 83.0 (C-10),
113.5, 117.5, 125.3, 126.0, 127.0, 127.3, 127.9, 128.2,
129.0, 130.1, 132.1, 133.1, 134.5, 142.5, 144.2, 145.7
(aromatic carbons), 160.5 (CO, b-lactam), 174.2, 175.1
(CO, imide); Anal. Calcd for C33H29ClN6O5: C, 63.41; H,
4.68; N, 13.44. Found: C, 64.19; H, 4.83; N, 12.95.
C-7), 6.7 (NCH3), 52.0 (C-9), 59.9 (C-4), 62.5 (C-3), 82.3 (C-
10), 111.1, 111.9, 120.7, 126.3, 127.1, 131.1, 132.8, 134.4,
134.7, 147.6, 148.8, 149.7 (aromatic carbons), 164.3 (CO, b-
lactam), 176.2, 176.5 (CO, imide); Anal. Calcd for
C35H35N7O5: C, 66.34; H, 5.57; N, 15.47. Found: C, 65.67;
H, 5.12; N, 14.76.
6-(1-(3,4-Dimethoxyphenethyl)-2-(4-(dimethylamino)phenyl)-
4-oxoazetidin-3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahy-
dro-4,8-methano[1,2,3]triazolo[4,5-f]isoindole-5,7(3aH,6H)-
dione (5g) Olive solid (yield 62 %, 0.4 g); mp: 223 °C
decomposed; IR (KBr, cm-1): 1596 (N=N), 1704 (CO
1
imide), 1758 (CO b-lactam); H-NMR (250 MHz, CDCl3)
d (ppm): 1.35 (1H, d, J = 11.37 Hz, H-11), 1.58 (1H, d,
J = 11.37 Hz, H-11), 2.82–2.92 (2H, m, H-13), 2.95 (6H,
s, NCH3), 3.10–3.17 (2H, m, H-5 and H-8), 3.30–3.36 (2H,
m, H-6 and H-7), 3.34, 3.86 (2H, 2m, H-12), 3,78, 3.86
(2H, 2 s, 2OCH3), 3.95, 4.74 (2H, 2d, J = 9.47 Hz, H-9
and H-10), 4.66 (1H, d, J = 2.21 Hz, H-4), 4.97 (1H, d,
J = 2.21 Hz, H-3), 6.62–6.76 (5H, m, ArH), 6.92 (2H, d,
J = 8.5 Hz, ArH), 7.30 (2H, d, J = 9.47 Hz, ArH), 8.23
(2H, d, J = 8.53 Hz, ArH); 13C NMR (62.9 MHz, CDCl3)
d (ppm): 33.6 (C-11), 35.5 (C-13), 40.3 (2NCH3), 42.2,
42.7 (C-5, C-8), 43.6 (C-12), 45.3, 45.6 (C-6, C-7), 55.1
(C-9), 55.8, 55.9 (2OCH3), 59.7 (C-4), 62.6 (C-3), 82.9 (C-
10), 111.2, 111.8, 112.3, 113.5, 120.8, 121.5, 126.0, 127.9,
130.9, 142.4, 144.2, 147.6, 148.8, 151.0 (aromatic car-
bons), 163.7 (CO, b-lactam), 174.3, 175.5 (CO, imide);
Anal. Calcd for C36H37N7O7: C, 63.61; H, 5.49; N, 14.42.
Found: C, 62.97; H, 4.82; N, 13.76.
6-(1-(Benzo[d][1,3]dioxol-5-yl)-2-(3,4-dimethoxyphenyl)-4-
oxoazetidin-3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahy-
dro-4,8-methano[1,2,3]triazolo[4,5-f]isoindole-5,7(3aH,6H)-
dione (5e) Yellow solid (yield 63 %, 0.4 g); mp: 206.5 °C
decomposed; IR (KBr, cm-1):1596 (N=N), 1712 (CO imide),
1758 (CO b-lactam); 1H-NMR d 250 MHz (DMSO-d6): 1.07
(1H, d, J = 11.05 Hz, H-11), 1.61 (1H, d, J = 11.05 Hz,
H-11), 3.05–3.18 (2H, m, H-5 and H-8), 3.43–3.54 (2H, m,
H-6 and H-7), 3.62, 3.69 (6H, 2 s, OCH3), 3.72, 4.79 (2H,
2d, J = 8.84 Hz, H-9, H-10), 5.09 (1H, d, J = 2.52 Hz,
H-4), 5.33 (1H, d, J = 2.52 Hz, H-3), 5.94 (2H, d,
J = 3.63 Hz, H-12), 6.59 (1H, d, J = 8.37 Hz, ArH), 6.86
(3H, t, ArH), 6.99–7.09 (2H, m, ArH), 7.25 (2H, d,
J = 8.37 Hz, ArH), 8.27 (2H, d, J = 8.37 Hz, ArH); 13C
NMR (62.9 MHz, DMSO-d6) d (ppm): 34.7 (C-11), 42.0,
42.8 (C-5, C-8), 45.1, 45.2 (C-6, C-7), 55.1 (C-9), 55.3
(OCH3), 59.1 (C-4), 62.1 (C-3), 83.0 (C-10), 99.3 (C-12),
101.2, 108.4, 110.2, 111.7, 111.8, 113.3, 119.3, 126.1,
126.2, 127.9, 131.1, 141.5, 143.8, 144.2, 148.9, 149.0
(aromatic carbons), 161.0 (CO, b-lactam), 175.3, 175.9
(CO, imide); Anal. Calcd for C33H28ClN6O9: C, 60.73; H,
4.32; N, 12.88. Found: C, 59.98; H, 4.35; N, 13.45.
6-(1-(2,4-Dimethoxyphenyl)-2-(3,4-dimethoxyphenyl)-4-
oxoazetidin-3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahy-
dro-4,8-methano[1,2,3]triazolo[4,5-f]isoindole-5,7(3aH,6H)-
dione (5h) Brown solid (yield 71 %, 0.5 g); mp: 163 °C
decomposed; IR (KBr, cm-1):1596 (N=N), 1712 (CO
imide), 1758 (CO b-lactam); 1H-NMR (250 MHz, CDCl3) d
(ppm): 1.35 (1H, d, J = 11.05 Hz, H-11), 1.59 (1H, d,
J = 11.05 Hz, H-11), 3.14–3.21 (2H, m, H-5 and H-8),
3.34–3.39 (2H, m, H-6 and H-7), 3.68, 3.70, 3.73, 3.74, 3.78,
3.80 (12H, 6 s, OCH3), 4.01, 4.79 (2H, 2d, J = 8.84 Hz,
H-9, H-10,), 5.02 (1H, d, J = 2.53 Hz, H-4), 5.43 (1H, d,
J = 2.53 Hz, H-3), 6.36–6.46 (2H, m, ArH), 6.60 (1H, s,
ArH), 6.71–6.86 (2H, m, ArH), 6.96 (1H, d, J = 9.32 Hz,
ArH), 7.27–7.36 (2H, m, ArH), 8.06 (2H, d, J = 8.21 Hz,
ArH); 13C NMR (62.9 MHz, CDCl3) d (ppm): 31.9 (C-11),
37.1, 37.9 (C-5, C-8), 47.1, 47.5 (C-6, C-7), 55.0 (C-9), 55.5,
55.7, 55.8 (4OCH3), 61.9 (C-4), 62.8 (C-3), 82.9 (C-10),
99.8, 104.7, 108.9, 111.2, 113.5, 119.3, 120.7, 125.1, 125.9,
142.3, 149.3, 149.4, 153.8, 153.9 (aromatic carbons), 159.3
(CO, b-lactam), 175.5, 175.7 (CO, imide); Anal. Calcd for
C34H32N6O9: C, 61.07; H, 4.82; N, 12.57. Found: C, 61.30;
H, 4.94; N, 11.75.
6-(1-(4-(Dimethylamino)phenyl)-2-(4-isopropylphenyl)-4-
oxoazetidin-3-yl)-1-(4-nitrophenyl)-1,4,4a,7a,8,8a-hexahydro-
4,8-methano[1,2,3]triazolo[4,5-f]isoindole-5,7(3aH,6H)-dione
(5f) Golden solid (yield 68 %, 0.4 g); mp: 223 °C
decomposed; IR (KBr, cm-1): 1596 (N=N), 1704 (CO
imide), 1751 (CO b-lactam); 1H-NMR (250 MHz, CDCl3) d
(ppm): 1.21 (6H, d, J = 6.95 Hz, H-13), 1.34 (1H, d,
J = 10.74 Hz, H-11), 1.57 (1H, d, J = 10.74 Hz, H-11),
2.87 (7H, s, H-12 and NCH3), 3.08–3.14 (2H, m, H-5 and
H-8), 3.31–3.37 (2H, m, H-6 and H-7), 3.99, 4.79 (2H, 2d,
J = 8.84 Hz, H-9 and H-10), 5.11 (1H, d, J = 2.52, H-4),
5.33 (1H, d, J = 2.52, H-3), 6.59 (2H, d, J = 7.74 Hz, ArH),
7.14–7.33 (8H, m, ArH), 8.20 (2H, d, J = 9.32 Hz, ArH);
13C NMR (62.9 MHz, CDCl3) d (ppm): 23.9 (C-13), 33.5 (C-
12), 33.8 (C-11), 42.2, 43.0 (C-5, C-8), 445.1, 45.2 (C-6,
123

Med Chem Res
Scheme 1 Synthesis of N-
endo-5-norbornene-2,3-
dicarboxyloylglycine
H
O
H
O
O
O
H
DMF, reflux
24
H
H2N
N
+
O
OH
OH
h
O
O
1
Fig. 1 X-ray crystal structures
of two conformers A and B of 1
Scheme 2 Synthesis of b-
lactams 3a–q
11
5
H
8
O
R2
7
9
H
O
N
H
R2
O
R1
H
4
N
10
6
2a-q
N
3
1
OH
N
O
R1
CH Cl r.t
TsCl, Et
,
2
3N,
2
O
2
O
3a-q
1
General procedure for the determination of MICs
against bacteria
performed in sterile 96-well microplates. All compounds
were solubilized in methanol at a concentration of 5 mg/
mL and were transferred to each microplate well (in all
cases, concentrations of the desired molecules in metha-
nol do not exceed 2 % of the total proportion), in order to
obtain a twofold serial dilution in 100 lL of broth, and
100 lL of inocula containing 2–6 105 CFU of each bac-
teria and yeast was added to each well. A number of wells
were reserved for positive controls, inoculum viability
and solvent effect. After 24 h of incubation, MIC was
defined for each agent from duplicate observations as the
lowest concentration of compound allowing no visible
growth.
Antimicrobial activity of the compounds was studied by the
determination of minimal inhibitory concentrations (MICs)
according to the NCCLS guidelines M7-A2 using the
microbroth dilution methods. The bacteria strains were
grown on trypticase soy agar (Becton–Dickinson) at 37 °C
for 24 h. Inocula were prepared in TCE (tryptone 0.1 %,
NaCl 8 %, wt/vol) by adjusting the turbidity at 623 nm to
obtain 1–3 105 CFU/mL.
Antimicrobial activities of the compounds were
determined by using a broth microdilution method
123

Med Chem Res
Table 1 Structures of b-lactams 3a–q
Yield (%)
Yield (%)
β-lactam
Structure
β-lactam
Structure
(cis/trans (%))
(cis/trans (%))
74(0/100)
73(0/100)
71(0/100)
45(0/100)
3a
3g
3b
3c
3h
86(100/0)
64(0/100)
3i
3d
3e
3f
82(0/100)
78(0/100)
62(0/100)
3j
3k
3l
65(0:100)
67(0/100)
86(100/0)
3m
84(0/100)
3p
3q
88(0/100)
90(100/0)
59(0/100)
57(0/100)
3n
3o
General procedure for antimalarial activity
measurements
medium consisting of RPMI 1640 (Invitrogen) supple-
mented with 27.5 mM NaHCO3, 20 mg/L gentamycin and
10 % human serum. Parasites were grown at 37 °C in
human O red blood cells at a 6 % hematocrit under a 5 %
CO2, 10 % O2 and 85 % N2 atmosphere. Cultures were
The chloroquine-resistant P. falciparum strain K14
(Southeast Asia) was cultured in vitro in a complete
123

Med Chem Res
synchronized by sorbitol treatments. Stock solutions of
lactam derivatives were prepared in sterile DMSO
(10 mM), and later dilutions were with complete culture
medium. Increasing concentrations of lactam derivatives
(100 lL/well, top concentration = 50 lM) were dis-
tributed in a 96-well plate; DMSO (0.5 % vol/vol, top
concentration) was distributed for control. Then, 100 lL
from a culture containing [95 % ring (0–20 h postinva-
sion) at a 0.8 % parasitemia and 3 % hematocrit in com-
plete medium was added per well along with 1.0 lCi of
3H-hypoxanthine with a specific activity of 14.1 Ci/mmol
(PerkinElmer, Courtaboeuf, France). Parasites were grown
for 42 h at 37 °C. Plates were then freeze-thawed and
harvested on filters. Dried filters were moistened in scin-
tillation liquid mixture (Microscint O; PerkinElmer) and
counted in a Top Count Microbeta counter (PerkinElmer).
Percentage growth inhibition was calculated from the
parasite-associated radioactivity. In the absence of lactam
derivatives, 100 % 3H-hypoxanthine incorporation was
determined from a control grown. The concentration of
drug giving 50 % inhibition of label incorporation (IC50)
was determined by nonlinear regression analysis of log-
based dose–response curve (Riasmart; Packard). Each
concentration was estimated from independent experiments
in triplicate.
endo-5-norbornene-2,3-dicarboxyloylglycine and p-tolue-
nesulfonyl chloride in the presence of triethylamine
(Scheme 2; Table 1).
The desired hybrids 5a–h were synthesized using the
1,3-dipolar cycloaddition reaction (Tarabara et al., 2009) of
1-azido-4-nitrobenzene 4 (prepared by using a literature
procedure) (Kamalraj et al., 2008) and b-lactams 3a–
h (Scheme 3; Table 2).
The cis or trans stereochemistry of the products 3a–
q and 5a–h was assigned on the basis of observed coupling
constant between b-lactam ring hydrogens. The structure
assigned to the hybrids 5 was confirmed based on spectral
data and analytical evidences.
Due to the presence of asymmetrically substituted triazole
1
fragment in the molecules 5a–h, their H-NMR spectra are
somewhat different from the 3a–h spectra and are affected
by the nonequivalent triazole fragment protons (H-9, H-10)
that resonate in the regions 3.72–4.26 and 4.76–4.85 ppm.
Their vicinal coupling constant 8.68–9.79 Hz is similar to
the systems bearing exo-oriented triazole fragment (Shea
and Kim, 1992). Furthermore, the position of the bridge
proton signals (H-11) that are nonequivalent is another
evidence of a preferential exo orientation of the synthesized
triazole ring.
Biological evaluations
Results and discussion
Chemistry
These newly synthesized b-lactamsand their triazole hybrids
were evaluated for their biological activities. Firstly, no
significant antimicrobial efficiency against Gram-positive S.
aureus (ATCC 25923) and Gram-negative bacteria E. coli
(ATCC 25922) or P. aeruginosa (ATCC 27853) and fungi
such as C. albicans (ATCC 90028) and C. glabrata (ATCC
90030) with MICs values less than 125 lg/mL have been
encountered. Nevertheless, moderate-to-good antimalarial
activities have been obtained against chloroquine-resistant
P. falciparum K14 strain as outlined in Table 3 with IC50
varying from 15 to 50 lM.
The precursor N-endo-5-norbornene-2,3-dicarboxyloyl-
glycine 1 was prepared according to a reported procedure
(Biagini et al., 1995) (Scheme 1).
The X-ray crystallography of 1 showed two conformers:
A, the norbornene and carboxylic acid groups lie to the
same side of the heterocycle, and B, they lie on opposite
sides (Akkurt et al., 2013) (Fig. 1).
The b-lactams 3a–q were synthesized by Staudinger
reaction of appropriately functionalized Schiff bases 2a–
q with ketene derived from 1, prepared in situ from N-
There is no clear structure–activity relationship (SAR)
dealing with our antimalarial activities results. Neverthe-
less, most of the compounds demonstrating a potent
N
N3
H
O
O
N
N
R2
H
R2
N
N
dry toluene
reflux, 24h
+
N
O
N
R1
O
R1
N
O2
O
NO2
O
3a-h
4
5a-h
Scheme 3 Synthesis of b-lactam-triazole hybrids 5a–h
123

Med Chem Res
Table 2 Structures of b-lactam-triazole hybrids 5a–h
Yield(%)
β-lactam
Structure
β-lactam
Structure
(cis/trans (%))
74(0/100)
78(0/100)
3a
5a
3b
3c
5b
71(0/100)
5c
78(0/100)
63(0/100)
3d
3e
5d
5e
68(0/100)
62(0/100)
3f
5f
5g
5h
3g
71(0/100)
3h
antimalarial activity possess a chlorophenyl moiety sug-
gesting a positive effect of this halogen group with respect
to the mechanism of action involved against the P. falci-
parum K14 strain.
chlorine group in 3m by an isopropyl one in 3g decreased
dramatically the biological activity encountered demon-
strating the important role of a chlorine atom in such
molecules.
Changing the isopropyl tertiary carbon in 3f to nitrogen
in 3j enhances the biological activity as well as enlarging
in 3m the carbon space between the nitrogen b-lactam ring
and the aryl group by two carbons. Substitution of the
Finally, adding a triazole moiety to 3a, 3g and 3h did
not lead to a significant enhancement of the biological
activity, whereas the presence of this group in 5b–5f
structure leads to a decrease in activity for 5d with respect
123

Med Chem Res
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Table 3 Antimalarial activities of b-lactams 3a–3q and triazole
hybrids 5a–5h
Compound
IC50 (lM)
P. falciparum K14
Compound IC50 (lM)
P. falciparum K14
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11
17.93
[50
[50
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[50
[50
[50
[50
[50
22.5
[50
3l
[50
22.11
[50
[50
27.2
3a
3b
3c
3d
3e
3f
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5a
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5d
5e
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34.6
21.6
42.6
48.9
34.2
3g
3h
3i
3j
5g
5h
[50
[50
3k
to 3d but to a three times improvement for all the other
compounds.
Conclusion
A series of novel b-lactams and their triazole conjugates
were synthesized via the [2 ? 2] ketene imine cycloaddi-
tion reaction. N-endo-5-norbornene-2,3-dicarboxyloyl-
glycine was the source of a special ketene used in these
syntheses. These derivatives demonstrated moderate-to-
good IC50 values varying from 15 to 50 lM against P.
falciparum K14-resistant strain. A rapid analysis of our
data has clearly demonstrated that the presence of a
chlorophenyl group associated with a p-methoxyphenyl
substituent on the b-lactam ring enhances the antimalarial
activity. Otherwise, it has been recently reported that azole
derivatives could be inhibitors of Falcipain-2, a papain
family cysteine protease and important hemoglobinase of
erythrocytic Plasmodium falciparum parasites (Kumar
et al., 2014a, b). In this context, further studies are now
under current investigation to elucidate the mechanism of
action involved by our molecules against Falcipain-2 in
order to improve their structure–activity relationships.
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Acknowledgments Funding for this research was generously pro-
vided by the Shiraz University Research Council (Grant No. 93-GR-
SC-23).
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