Synthesis of some new monocyclic β-lactams as antimalarial agents

Article abstract of DOI:10.1007/s13738-015-0685-x

A series of new monocyclic β-lactams bearing several methoxy groups and possessing a similar meticillin structure was prepared by the ketene-imine [2+2] cycloaddition reaction (Staudinger reaction). The cycloaddition reaction was found to be totally diast

Full text of DOI:10.1007/s13738-015-0685-x

J IRAN CHEM SOC
DOI 10.1007/s13738-015-0685-x
ORIGINAL PAPER
Synthesis of some new monocyclic β‑lactams as antimalarial
agents
Aliasghar Jarrahpour1 · Malihe Aye1 · Véronique Sinou2 · Christine Latour2 ·
Jean Michel Brunel3,4,5,6
Received: 30 November 2014 / Accepted: 15 June 2015
© Iranian Chemical Society 2015
Abstract A series of new monocyclic β-lactams bearing
several methoxy groups and possessing a similar meticillin
structure was prepared by the ketene–imine [2+2] cycload-
dition reaction (Staudinger reaction). The cycloaddition
reaction was found to be totally diastereoselective for 3a‑l
(electron donating phenoxy ketenes) and 3u leading exclu-
sively to the formation of cis-β-lactams while 3m‑o, 3q‑s,
and 3v‑x were formed as trans diastereomer. β-lactams 3p,
3t, and 3y were found to be a mixture of cis/trans diastere-
omers. Compounds 3a‑x were tested against chloroquine-
resistant p. falciparum K14 strain and showed low to excel-
lent activities with IC50 varying from 5 to 50 µM.
Introduction
Due to their important biological activities, β-lactams
are one of the best known and most extensively studied
classes of antibiotics [1]. These classes of drugs have
revolutionized treatment in medicine [2]. The azetidi-
none ring is responsible for the antibacterial and other
biological activities and variable side chains that account
for the major differences in their chemical and pharma-
cological properties [3]. 2-Azetidinones are susceptible
to ring cleavage reactions, due to ring strain. This prop-
erty has been discussed by some research groups who
have utilized the β-lactam as a synthon for a wide vari-
ety of compounds [4, 5]. Bacteria have enhanced their
resistance against the most common antibacterial drugs.
In particular, meticillin-resistant staphylococci represent
one of the most challenging and threatening diseases
globally [6, 7]. Meticillin is insensitive to beta-lacta-
mase enzymes secreted by many penicillin-resistant bac-
teria. The presence of the ortho-dimethoxyphenyl group
directly attached to the side chain carbonyl group of the
penicillin nucleus facilitates the β-lactamase resistance,
since those enzymes are relatively intolerant of side-
chain steric hindrance. Movement of one of the methoxy
groups to the para position or replacing one of them by
a hydrogen results in an analog sensitive to β-lactamase.
Putting in a methylene between the aromatic ring and
6-APA likewise produces a β-lactamase sensitive agent.
These findings provide strong support for the hypoth-
esis that resistance to enzyme degradation is based on
differential steric hindrance [8, 9]. In this context, we
have envisioned the synthesis of 2-azetidinones bearing
methoxy groups at different positions to mimic meticil-
lin structure.
Keywords Β-lactam · Meticillin · Staudinger reaction ·
P. falciparum · Dimethoxyaniline
* Aliasghar Jarrahpour
jarrah@susc.ac.ir; aliasghar6683@yahoo.com
1
Department of Chemistry, College of Sciences, Shiraz
University, Shiraz, Iran
2
UMR-MD3 Relation hôte-parasites, Physiopathologie
and Pharmacologie, Faculté de pharmacie, Aix-Marseille
Université, Bd Jean Moulin, 13385 Marseille, France
3
Centre de Recherche en Cancérologie de Marseille (CRCM),
CNRS, UMR7258, Bd Jean Moulin, 13385 Marseille, France
4
Institut Paoli Calmettes, Marseille, France
5
Aix-Marseille Université, UM 105, Marseille, France
6
Inserm, U1068, Faculté de pharmacie, Bd Jean Moulin,
13385 Marseille, France
1 3

J IRAN CHEM SOC
calcd. for C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C,
Experimental section
General
62.42; H, 4.04; N, 5.68; GC–MS (m/z) = 420 [M+].
1‑(3,4‑Dimethoxyphenyl)‑4‑(3‑nitrophenyl)‑3‑
phenoxyazetidin‑2‑one (3b)
All required chemicals were purchased from the Merck,
Fluka, Aldrich and Acros chemical companies. Dichlo-
romethane and triethylamine were dried by distillation over
CaH2 and then stored over 4Å molecular sieves. IR spectra
were run on a Shimadzu FT-IR 8300 spectrophotometer.
1H-NMR and 13C-NMR spectra were recorded in CDCl3 or
DMSO-d6 using a Bruker Avance DPX instrument (operating
Yield: 80 %; mp: 144–146 °C; IR (KBr) cm−1: 1766 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.78,3.83 (OMe, s, 6H),
5.49 (H-4, d, 1H, J = 4.80), 5.64 (H-3, d, 1H, J = 4.80),
6.43–8.24 (ArH, m, 12H); 13C-NMR (CDCl3) δ 56.04,
56.06 (2 OCH3), 61.15 (C-4), 81 (C-3), 102.61, 108.32,
111.27, 115.40, 122.61, 123.29, 123.83, 128.80, 129.49,
130.89, 133.88, 135.37, 146.52, 148.18, 149.68, 156.38
(aromatic carbons), 162.02 (CO, β-lactam); Anal. calcd. for
C23H20N2O6: C, 65.71; H, 4.79; N, 6.66;. Found: C, 65.51;
H, 4.66; N, 5.83; GC–MS (m/z) = 420 [M+].
1
at 250 MHz for H and 62.9 MHz for 13C). Chemical shifts
were reported in ppm (δ) downfield from TMS. All values of
the coupling constants (J) are in Hertz. The mass spectra were
recorded on a Shimadzu GC–MS QP 1000 EX instrument.
Melting points were determined in open capillaries with
a Buchi 510 melting point apparatus and are not corrected.
Thin-layer chromatography was carried out on silica gel F254
analytical sheets obtained from Fluka. Column chromatogra-
phy was performed on Merck Kieselgel (230–270 mesh).
1‑(3,4‑Dimethoxyphenyl)‑4‑(4‑nitrophenyl)‑3‑phenoxyaze‑
tidin‑2‑one (3c)
Yield: 79 %; mp: 131–133 °C; IR (KBr) cm−1: 1755 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.72,3.77 (OMe, s, 6H),
General procedure for the synthesis of Schiff bases 1a‑p
5.41 (H-4, d, 1H, J = 4.85), 5.56 (H-3, d, 1H, J = 4.85),
6.29–8.08 (ArH, m, 12H); 13C-NMR (CDCl3) δ 56, 56.04
(2 OCH3), 61.19 (C-4), 81.16 (C-3), 102.49, 108.27,
111.21, 115.40, 122.63, 123.58, 128.98, 129.48, 130.20,
140.46, 146.48, 148.11, 149.62, 156.45 (aromatic carbons),
161.98 (CO, β-lactam); Anal. calcd. for C23H20N2O6: C,
65.71; H, 4.79; N, 6.66. Found: C, 64.39; H, 4.71; N, 7.23;
GC–MS (m/z) = 420 [M+].
A mixture of dimethoxyaniline (20.00 mmol) and a substi-
tuted benzaldehyde (20.00 mmol) was refluxed in ethanol
(25 mL) for 2–4 h. After cooling the solution, the precipi-
tate formed was filtered off and washed with ethanol to
give pure Schiff bases as colored solids or crystals in excel-
lent yields.
General procedure for the synthesis of β‑lactams 3a‑y
1‑(2,4‑Dimethoxyphenyl)‑4‑(3,4‑dimethoxyphenyl)‑3‑
phenoxyazetidin‑2‑one (3d)
A solution of pure or crude Schiff base (1.0 eq.) was stirred
with the corresponding substituted acetic acid (1.5 eq.),
p-toluenesulfonyl chloride (1.5 eq.) and triethylamine
(4–5 eq.) in dry CH2Cl2 at room temperature. After 24 h,
the mixture was washed with HCl 1 N, saturated sodium
bicarbonate solution and brine, dried over sodium sulfate
and the solvent was evaporated to give the crude product
which was then purified by recrystallization from EtOAc,
EtOH and MeOH.
Yield: 45 %; mp: 116–118 °C; IR (KBr) cm−1: 1758 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.64–3.70 (OMe, s, 12H),
5.51 (H-3, 4, s, 2H, J = 4.35), 6.30–7.59 (ArH, m, 11H);
13C-NMR (CDCl3) δ 55.48, 55.55, 55.68, 55.86 (4 OCH3),
64.94 (C-4), 82.01 (C-3), 99.64, 104.46, 110.44, 111.22,
115.51, 117.75, 121.19, 121.88, 125.30, 126.44, 128.78,
129.20, 130.89, 148.47, 148.90, 153.00, 157.02, 158.89
(aromatic carbons), 164.58 (CO, β-lactam); Anal. calcd. for
C25H25NO6: C, 68.95; H, 5.79; N, 3.22. Found: C,68.47; H,
5.93; N, 3.73; GC–MS (m/z) = 420 [M+].
1‑(3,4‑Dimethoxyphenyl)‑4‑(2‑nitrophenyl)‑3‑
phenoxyazetidin‑2‑one (3a)
Yield 65 %; mp: 183–185 °C; IR (KBr) cm−1: 1751 (CO,
β-lactam); 1H-NMR (CDCl3) δ 3.76, 3.80 (OMe, s, 6H), 5.62
(H-4, d, H, J = 5.25), 6.08 (H-3, d, 1H, J = 5.25), 6.44–
8.16 (ArH, m, 12H); 13C-NMR (CDCl3) δ 56.05, 59.23 (2
OCH3), 68.12 (C-4), 82.14 (C-3), 102.27, 108.27, 111.27,
116.37122.76, 125.38138.78, 129.23, 129.30, 129.46,
130.13, 13073, 130.88, 133.96, 146.41, 148.18, 149.66,
157.18 (aromatic carbons), 163.37 (CO, β-lactam); Anal.
1,4‑Bis(3,4‑dimethoxyphenyl)‑3‑phenoxyazetidin‑2‑one
(3e)
Yield: 75 %; mp: 123–125 °C; IR (KBr) cm−1: 1755 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.69–3.76 (OMe, s, 12H),
5.23 (H-4, d, 1H, J = 4.70), 5.48 (H-3, d, 1H, J = 4.70),
6.50–7.29 (ArH, m, 11H); 13C-NMR (CDCl3) δ 55.77–
56.00 (4 OCH3), 62.20 (C-4), 81.06 (C-3), 102.52, 108.73,
1 3

J IRAN CHEM SOC
110.72, 110.86, 111.1, 115.57, 120.97, 122.15, 124.97,
129.28, 130.85, 146.07, 148.88, 149.31 (aromatic carbons),
162.65 (CO, β-lactam); Anal. calcd. for C25H25NO6: C,
68.95; H, 5.79; N, 3.22. Found: C,68.75; H, 5.56; N, 2.90.
(H-3, d, 1H, J = 2.59), 6.30 (H-4, d, 1H, J = 2.42), 6.40–8.14
(ArH, m, 12H); 13C-NMR (CDCl3) δ 54.43, 54.45 (2 OCH3),
63.16 (C-4), 80.1 (C-3), 98.52, 103.64, 114.25, 116.33,
120.60, 121.23, 121.43, 122.21, 122.34, 122.65, 123.89,
127.97, 128.35, 133.15, 135.84, 146.84, 151.41, 155.40,
157.96 (aromatic carbons), 162.86 (CO, β-lactam); Anal.
calcd. for C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found:
C,65.93; H, 5.88; N, 5.86; GC–MS (m/z) = 420 [M+].
1‑(2,4‑Dimethoxyphenyl)‑4‑(2‑methoxyphenyl)‑3‑
phenoxyazetidin‑2‑one (3f)
Yield: 50 %; mp: 108–110 °C; IR (KBr) cm−1: 1743 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.66–3.72 (OMe, d, 9H),
1‑(3,4‑Dimethoxyphenyl)‑4‑(2‑methoxyphenyl)‑3‑
5.58 (H-4, dd, 1H, J = 2.62), 5.61 (H-3, dd, 1H, J = 2.12),
6.36–7.72 (ArH, m, 12H); 13C-NMR (CDCl3) δ 55.15–
55.50 (3 OCH3), 65.06 (C-4), 82.15 (C-3), 99.74, 104.49,
113.74, 113.85, 115.66, 117.89, 120.12, 120.78, 125.17,
128.94, 129.18, 135.79, 152.80, 157.08, 158.77, 159.23
(aromatic carbons), 167.55 (CO, β-lactam); Anal. calcd. for
C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found: C, 70.73;
H, 5.88; N, 3.98; GC–MS (m/z) = 405 [M+].
phenoxyazetidin‑2‑one (3j)
Yield 77 %; mp: 168–170 °C; IR (KBr) cm−1: 1755
1
(CO, β-lactam); H-NMR (CDCl3) δ 3.69–3.77 (OMe,
s, 9H), 5.49 (H-4, d, 1H, J = 4.82), 5.73 (H-3, d, 1H,
J = 4.82), 6.48–7.32 (ArH, m, 12H); 13C-NMR (CDCl3)
δ 55.15, 55.95, 56.03 (3 OCH3), 56.46 (C-4), 81.08
(C-3), 102.35, 108.66, 110.03, 111.24, 115.73, 120.42,
120.62, 121.91, 128.23, 129.01, 129.48, 130.93, 145.98,
149.37, 157.16, 157.30 (aromatic carbons), 162.92 (CO,
β-lactam); Anal. calcd. for C24H23NO5: C, 71.10; H,
5.72; N, 3.45. Found: C, 70.43; H, 5.75; N, 3.79; GC–
MS (m/z) = 405 [M+].
1‑(2,4‑Dimethoxyphenyl)‑4‑(3‑methoxyphenyl)‑3‑
phenoxyazetidin‑2‑one (3 g)
Yield: 20 %; mp: 98–100 °C; IR (KBr) cm−1: 1747 (CO,
β-lactam); 1H-NMR (CDCl3) δ 3.61, 3.68, 3.73 (OMe, t, 9H),
5.56 (H-4, m, 1H), 6.13 (H-3, t, 1H), 6.35–7.82 (ArH, m, 12H);
13C-NMR (CDCl3) δ 55.12, 55.49, 55.55 (3 OCH3), 59.59
(C-4), 82.16 (C-3), 99.75, 104.56, 109.91, 115.64, 118.44,
120.13, 121.64, 122.66, 124.88, 128.10, 128.93, 152.68, 157.22,
157.27, 158.53 (aromatic carbons), 164.78 (CO, β-lactam);
Anal. calcd. for C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found:
C,70.50; H, 5.44; N, 3.32; GC–MS (m/z) = 405 [M+].
1‑(3,4‑Dimethoxyphenyl)‑4‑(3‑methoxyphenyl)‑3‑
phenoxyazetidin‑2‑one (3 k)
Yield 65 %; mp: 114–116 °C; IR (KBr) cm−1: 1745 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.65–3.75 (OMe, s, 9H),
5.25 (H-4, d, 1H, J = 4.81), 5.48 (H-3, d, 1H, J = 4.81),
6.46–7.27 (ArH, m, 12H); 13C-NMR (CDCl3) δ 55.25,
55.92, 56.01 (3 OCH3), 62.19 (C-4), 81.15 (C-3), 102.51,
108.71, 111.21, 113.61, 114.33, 115.74, 120.56, 122.18,
129.25, 129.42, 130.79, 134.30, 146.09, 149.35, 157.00,
159.57 (aromatic carbons), 162.59 (CO, β-lactam); Anal.
calcd. for C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found:
C, 70.14; H, 5.91; N, 5.27; GC–MS (m/z) = 405 [M+].
1‑(2,4‑Dimethoxyphenyl)‑4‑(2‑nitrophenyl)‑3‑
phenoxyazetidin2‑one (3 h)
Yield: 75 %; mp: 128–130 °C; IR (KBr) cm−1: 1743 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.50, 3.71 (OMe, s, 6H),
6.36 (H-4, d, 1H, J = 5.11), 5.66 (H-3, d, 1H, J = 5.11),
6.31–8.01 (ArH, m, 12H); 13C-NMR (CDCl3) δ 55.42,
55.54 (2 OCH3), 61.77 (C-4), 83.28 (C-3), 99.72, 104.75,
116.23, 122.45, 124.09, 124.81, 128.79, 128.90, 129.37,
130.88, 132.07, 133.43, 151.80, 157.24, 158.52 (aro-
matic carbons), 164.67 (CO, β-lactam); Anal. calcd. for
C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C,62.42;
H, 4.04; N, 5.68; GC–MS (m/z) = 420 [M+].
1‑(3,4‑Dimethoxyphenyl)‑4‑(4‑methoxyphenyl)‑3‑
phenoxyazetidin‑2‑one (3 l)
Yield: 50 %; mp: 123–125 °C; IR (KBr) cm−1: 1745 (CO,
1
β-lactam); H-NMR (CDCl3) δ 3.65–3.75 (OMe, s, 12H),
5.24 (H-4, d, 1H, J = 4.72), 5.44 (H-3, d, 1H, J = 4.72),
6.48–7.61 (ArH, 12 m, H); 13C-NMR (CDCl3) δ 55.17-
61.92 (4 OCH3), 68.12 (C-4), 81.16 (C-3), 102.53, 108.75,
111.15, 113.84, 115.67, 122.11, 124.46, 128.78, 129.25,
129.43, 130.88, 145.99, 149.30,156.99, 159.85 (aro-
matic carbons), 162.70 (CO, β-lactam); Anal. calcd. for
C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found: C,70.90; H,
5.26; N, 5.97.
1‑(2,4‑Dimethoxyphenyl)‑4‑(3‑nitrophenyl)‑3‑
phenoxyazetidin‑2‑one (3i)
Yield: 80 %; mp: 131–133 °C; IR (KBr) cm−1: 1758 (CO,
β-lactam); 1H-NMR (CDCl3) δ 3.63, 3.69 (OMe, s, 6H), 5.60
1 3

J IRAN CHEM SOC
2‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(2‑nitrophenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3 m)
OCH3), 59.033, 60.40 (C-4), 60.58, 61.11 (C-3), 99.83,
104.61, 109.01, 110.38, 118.77, 120.22, 120.46, 123.13,
123.55, 124.70, 125.43, 125.47, 127.05, 127.82, 129.23,
131.31, 131.84, 134.06, 134.46, 153.40, 157.14, 158.63,
158.75 (aromatic carbons), 163.13 (2 CO, β-lactam); Anal.
calcd. for C26H22N2O6: C, 68.11; H, 4.84; N, 6.11. Found:
C, 67.22; H, 4.90; N, 6.18; GC–MS (m/z) = 458 [M+].
Yield: 85 %; mp: 227–229 °C; IR (KBr) cm−1: 1720 (CO,
β-lactam), 1750-1780 (CO, Phth); 1H-NMR (CDCl3) δ
3.47, 3.72 (OMe, d, 6H), 5.21 (H-2, d, 1H, J = 2.32),
6.10 (H-3, d, 1H, J = 1.98), 5.97–8.36 (ArH, m, 11H);
13C-NMR (CDCl3) δ 55.59, 59.99 (2 OCH3), 62.43 (C-3),
62.90 (C-2), 99.76, 104.86, 123.55, 123.78, 124.01,
124.49, 124.73, 125.00, 126.62, 128.77, 128.80, 130.27,
130.87, 131.23, 133.38, 134.28, 134.43, 152.30, 158.72
(aromatic carbons), 162.80, 163.18 (2 CO, Phth), 166.96
(CO, β-lactam); Anal. calcd. for C25H19N3O7: C, 63.42; H,
4.05; N, 8.88. Found: C, 57.53; H, 3.38; N, 10.97; GC–MS
(m/z) = 473 [M+].
2‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(3‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3q)
Yield: 60 %; mp: 118–120 °C; IR (KBr) cm−1: 1720 (CO,
β-lactam), 1750–1770 (CO, Phth); 1H-NMR (CDCl3)
δ 3.59, 3.68, 3.69 (OMe, s, 9H), 5.22 (H-2, d, 1H,
J = 2.54), 5.57 (H-3, d, 1H, J = 2.54), 6.32–7.82 (ArH,
m, 11H); 13C-NMR (CDCl3) δ 55.17, 55.49, 55.72 (3
OCH3), 63.90 (C-3), 68.13 (C-2), 99.84, 104.62, 111.63,
114.03, 117.90, 118.8, 123.70, 125.15, 128.79, 129.95,
130.90, 131.78, 134.46, 138.67, 153.61, 158.96, 159.99
(aromatic carbons), 162.78,166.91 (2 CO, Phth), 167.76
(CO, β-lactam); Anal. calcd. for: C26H22N2O6: C, 68.11;
H, 4.84; N, 6.11. Found: C, 67.51; H, 4.86; N, 7.94; GC–
MS (m/z) = 458 [M+].
2‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(3‑nitrophenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3n)
Yield: 65 %; mp: 220–218 °C; IR (KBr) cm−1: 1720 (CO,
1
β-lactam), 1760–1775 (CO, Phth); H-NMR (DMSO) δ
3.62, 3.71 (OMe, s, 6H), 5.26 (H-2, d, 1H, J = 2.50), 5.81
(H-3, d, 1H, J = 2.50), 6.45–8.36 (ArH, m, 11H); 13C-
NMR (DMSO) δ 55.34, 55.70 (2 OCH3), 61.84 (C-3),
62.02 (C-2), 99.61, 105.26, 117.07, 121.91, 123.12, 123.43,
124.56, 130.10, 131.41, 133.09, 134.32, 139.74, 147.81,
152.74, 158.49 (aromatic carbons), 162.12 (2 CO, Phth),
166.66 (CO, β-lactam); Anal. calcd. for C25H19N3O7: C,
63.42; H, 4.05; N, 8.88. Found: C, 63.28; H, 4.17; N, 6.75.
2‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(4‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3r)
Yield: 85 %; mp: 184–186 °C; IR (KBr) cm−1: 1716 (CO,
β-lactam), 1755–1775 (CO, Phth); 1H-NMR (CDCl3)
δ 3.63, 3.65 (OMe, s, 9H), 5.19 (H-2, d, 1H, J = 2.55),
5.53 (H-3, d, 1H, J = 2.55), 6.28–7.76 (ArH, m, 11H);
13C-NMR (CDCl3) δ 55.21, 55.44, 55.70 (3 OCH3), 62.54
(C-3), 63.58 (C-2), 99.76, 104.56, 114.22, 117.75, 123.61,
125.24, 127.71, 128.79, 131.69, 134.45, 153.63, 158.92,
159.76 (aromatic carbons), 162.86 (2 CO, Phth), 166.92
(CO, β-lactam); Anal. calcd. for: C26H22N2O6: C, 68.11; H,
4.84; N, 6.11. Found: C, 67.02; H, 4.81; N, 5.93; GC–MS
(m/z) = 458 [M+].
2‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(4‑nitrophenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3o)
Yield: 60 %; mp: 186–188 °C; IR (KBr) cm−1: 1720 (CO,
β-lactam), 1770–1782 (CO, Phth); 1H-NMR (CDCl3) δ
3.64, 3.77 (OMe, s, 6H), 5.27 (H-2, d, 1H, J = 2.65), 5.76
(H-3, d, 1H, J = 2.65), 6.38–8.21 (ArH, m, 11H); 13C-
NMR (CDCl3) δ 55.56-55.60 (2 OCH3), 62.64 (C-3), 63.40
(C-2), 99.83, 104.85, 123.86, 124.24, 124.81, 126.99,
131.64, 134.66, 144.74, 147.96, 152.88, 159.07 (aromatic
carbons), 162.04 (2 CO, Phth), 166.76 (CO, β-lactam);
Anal. calcd. for C25H19N3O7: C, 63.42; H, 4.05; N, 8.88.
Found: C, 62.37; H, 3.87; N, 10.84.
2‑(1‑(3,4‑Dimethoxyphenyl)‑2‑(2‑nitrophenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3 s)
Yield: 25 %; mp: 203–205 °C; IR (KBr) cm−1: 1720 (CO,
1
β-lactam), 1755, 1762 (CO, Phth); H-NMR (CDCl3) δ
2‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(2‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3p)
3.55, 3.85 (OMe, s, 6H), 5.32 (H-2, d, 1H, J = 2.62), 5.93
(H-3, d, 1H, J = 2.62), 6.05–8.12 (ArH, m, 11H); 13C-
NMR (CDCl3) δ 55.92,56.08 (2 OCH3), 57.62 (C-3), 62.24
(C-2), 102.72, 108.65, 111.31, 123.53, 123.61, 123.69,
125.02, 125.77, 127.56, 129.52, 129.62, 131.24, 131.74,
131.99, 133.77, 134.24, 134.32, 134.42, 134.58, 149.66
(aromatic carbons), 161.95 (2 CO, Phth), 166.95 (CO,
β-lactam); Anal. calcd. for C25H19N3O7: C, 63.42; H, 4.05;
N, 8.88. Found: C, 62.11; H, 3.86; N, 8.64.
Mixture of cis and trans, yield 75 %; mp: 179–181 °C; IR
(KBr) cm−1: 1716 (CO, β-lactam), 1758–1770 (CO, Phth);
1H-NMR (CDCl3) δ 3.55–3.73 (OMe, s, 18H), trans: 5.31
(H-4, d, H, J = 2.70), 5.82 (H-3, d, 1H, J = 2.70), cis: 5.74
(H-4, d, 1H, J = 5.44), 5.95 (H-3, d, 1H, J = 5.44), 6.33–
8.08 (ArH, m, 22H); 13C-NMR (CDCl3) δ 55.01, 55.77 (3
1 3

J IRAN CHEM SOC
2‑(1‑(3,4‑Dimethoxyphenyl)‑2‑(3‑nitrophenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3t)
(ArH, m, 11H); 13C-NMR (CDCl3) δ 55.31, 55.88, 56.03 (3
OCH3), 61.45 (C-3), 62.60 (C-2), 102.59, 108.88, 111.26,
111.77, 114.41, 118.44, 123.80, 130.51, 131.02, 131.68,
134.25, 134.57, 137.47, 146.04, 149.30 (aromatic carbons),
160.36, 161.57 (2 CO, Phth), 166.8 (CO, β-lactam); Anal.
calcd. for C26H22N2O6: C, 68.11; H, 4.84; N, 6.11. Found:
C,66.40; H, 4.70; N, 6.32; GC–MS (m/z) = 458 [M+].
Mixture of cis and trans, yield: 50 %; mp: 148–150 °C; IR
(KBr) cm−1: 1720 (CO, β-lactam), 1755–1770 (CO, Phth);
1H-NMR (CDCl3) δ 3.73, 3.83 (OMe, s, 6H), trans: 5.21
(H-2, d, 1H, J = 2.56), 5.41 (H-3, d, 1H, J = 2.56), cis:
5.48 (H-2, d, 1H, J = 5.59), 5.70 (H-3, d, 1H, J = 5.59),
6.30–8.19 (ArH, m, 11H); 13C-NMR (CDCl3) δ 55.97-
60.28 (2 OCH3), 60.48 (C-3), 62.56 (C-2), 102.40, 102.77,
107.89, 108.59, 111.22, 121.49, 122.40, 123.52, 123.70,
123.91, 124.13, 129.64, 130.29, 130.69, 130.86, 131.51,
131.94, 133.39, 134.60, 134.76, 138.31, 146.41, 148.81,
149.56 (aromatic carbons), 160.03,161.02 (2 CO, Phth),
166.72 (CO, β-lactam); Anal. calcd. for C25H19N3O7: C,
63.42; H, 4.05; N, 8.88. Found: C, 62.94; H, 4.11; N, 8.64.
2‑(1‑(3,4‑Dimethoxyphenyl)‑2‑(4‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3x)
Yield: 80 %; mp: 186–188 °C; IR (KBr) cm−1: 1716 (CO,
β-lactam), 1755–1775 (CO, Phth); 1H-NMR (CDCl3) δ
3.73–3.76 (OMe, s, 9H), 5.19 (H-2, d, 1H, J = 2.57), 5.22
(H-3, d, 1H, J = 2.57), 6.50–7.81 (ArH, m, 11H); 13C-
NMR (CDCl3) δ 55.10-56.02 (3 OCH3), 61.16 (C-3), 62.75
(C-2), 102.44, 108.93, 111.23, 113.89, 114.74, 123.75,
127.60, 128.52, 131.02, 131.67, 134.25, 134.54, 145.95,
149.26 (aromatic carbons), 160.18, 161.70 (2 CO, Phth),
166.85 (CO, β-lactam); Anal. calcd. for C26H22N2O6: C,
68.11; H, 4.84; N, 6.11. Found: C,67.02; H, 4.81; N, 5.93;
GC–MS (m/z) = 458 [M+].
2‑(1‑(3,4‑Dimethoxyphenyl)‑2‑(4‑nitrophenyl)‑4‑oxoazeti‑
din‑3‑yl)isoindoline‑1,3‑dione (3u)
Yield: 58 %; mp: 244–246 °C; IR (KBr) cm−1: 1716 (CO,
β-lactam), 1762–1775 (CO, Phth); 1H-NMR (CDCl3) δ
3.78, 3.85 (OMe, s, 6H), 5.47 (H-2, d, 1H, J = 5.63), 5.70
(H-3, d, 1H, J = 5.63), 6.34-8.02 (ArH, m, 11H); 13C-
NMR (CDCl3) δ 56.12 (2 OCH3), 58.78 (C-3), 60.39 (C-2),
102.43, 107.86, 111.25, 123.74, 123.79, 128.36, 130.80,
130.90, 134.69, 140.00, 146.49, 147.86,149.78 (aromatic
carbons), 159.8 (2 CO, Phth), 166.60 (CO, β-lactam); Anal.
calcd. for C25H19N3O7: C, 63.42; H, 4.05; N, 8.88. Found:
C, 62.80; H, 4.36; N, 6.65; GC–MS (m/z) = 458, 473 [M+].
2‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(4‑nitrophenyl)‑4‑oxoazeti‑
din‑3‑yl)‑4‑nitroisoindoline‑1,3‑dione (3y)
Mixture of cis and trans, yield: 80 %; mp: 190–192 °C
(trans), 194–196 °C (cis); IR (KBr) cm−1: 1735 (CO,
β-lactam), 1785–1787 (CO, Phth); 1H-NMR (CDCl3) δ
3.55, 3.69 (OMe, s, 6H), trans: 5.20 (H-2, d, 1H, J = 1.70),
5.70 (H-3, d, 1H, J = 2.07), cis: 5.72 (H-2, d, 1H,
J = 5.56), 5.88 (H-3, d, 1H, J = 5.56), 6.29–8.13 (ArH,
m, 10H); 13C-NMR (CDCl3) δ 55.54 (2 OCH3), 62.72
(C-3), 63.02 (C-2), 99.71, 104.85, 117.29, 124.26, 124.70,
127.06, 127.62, 129.19, 133.57, 136.13, 144.29, 145.23,
148.02, 152.77, 159.14 (aromatic carbons), 161.10 (2 CO,
Phth), 164.28 (CO, β-lactam); Anal. calcd. for C25H18N4O9:
C, 57.92; H, 3.50; N, 10.81. Found: C,56.28; H, 4.48; N,
9.91; GC–MS (m/z) = 518 [M+].
2‑(1‑(3,4‑Dimethoxyphenyl)‑2‑(2‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3v)
Yield: 45 %; mp: 208–210 °C; IR (KBr) cm−1: 1720 (CO,
β-lactam), 1751–1760 (CO, Phth); 1H-NMR (CDCl3) δ
3.59, 3.77, 3.83 (OMe, s, 9H), 5.57 (H-2, d, 1H, J = 2.55),
5.70 (H-3, d, 1H, J = 2.55), 6.53–7.58 (ArH, m, 11H); 13C-
NMR (CDCl3) δ 55.05, 56.07 (3 OCH3), 57.71 (C-3), 57.93
(C-2), 102.40, 108.23, 109.23, 111.20, 120.33, 120.49,
123.26, 128.82, 129.35, 131.26, 131.68, 13413, 145.91,
149.45, 156.55 (aromatic carbons), 161.55 (2 CO, Phth),
166.33 (CO, β-lactam); Anal. calcd. for: C26H22N2O6: C,
68.11; H, 4.84; N, 6.11. Found: C, 66.67; H, 4.93; N, 6063;
GC–MS (m/z) = 458 [M+].
General procedure for dephthaloylation of monocyclic
β‑lactams
Method A
A mixture of monocyclic β-lactam 3n (1.50 mmol),
methanol (25.00 mL) and 0.12 mL (2.55 mmol) of
hydrazine hydrate was refluxed for 1 h. After evapora-
tion of the solvent, CHCl3 (20.00 mL) was added and
2,3-dihydrophthalazine-1,4-dione formed was filtered.
The filtrate was washed with saturated sodium bicarbo-
nate solution and brine, dried over sodium sulfate and
2‑(1‑(3,4‑Dimethoxyphenyl)‑2‑(3‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)isoindoline‑1,3‑dione (3w)
Yield: 70 %; mp: 183–185 °C; IR (KBr) cm−1: 1720 (CO,
β-lactam), 1760–1770 (CO, Phth); 1H-NMR (CDCl3) δ 3.77–
3.84 (OMe, s, 9H), 5.29 (H-2, 3, d, 2H, J = 2.63), 6.54–7.89
1 3

J IRAN CHEM SOC
the solvent was evaporated to give the crude product of
3-amino azetidin-2-one. Compounds xxxx were treated
by this method.
N‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(2‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)‑2,6‑dimethoxybenzamide (5b)
Mixture of cis and trans. yield: 30 %; mp: 110–112 °C;
IR (KBr) cm−1: 1687 (CO, Amide), 1755 (CO, β-lactam),
2950 (NH); 1H-NMR (CDCl3) δ 3.61–3.84 (OMe, s, 15H),
5.03, 5.13 (H-3, dd, 1H, J = (2.25, 8.96), (2.50, 9.77)),
5.41, 5.50 (H-2, d, 1H, J = 2.21, 2.25), 6.30–7.92 (ArH, m,
10H), 8.25, 8.36 (NH, d); Anal. calcd. for C27H28N2O7: C,
65.84; H, 5.73; N, 5.69. Found: C, 63.46; H, 6.42; N, 5.11.
Method B
A mixture of monocyclic β-lactam 3o (1.00 mmol), CH2Cl2
(25.00 mL) and methylhydrazine (0.05 mL,1.10 mmol)was
stirred for 3 days. Then the methylphthalhydrazide formed
was filtered. The filtrate was washed with saturated sodium
bicarbonate, solution, brine and dried over sodium sulfate
and the solvent was evaporated to give the crude product
of 3-amino-azetidin-2-one 4d which was then purified by
column chromatography. β-Lactams xxxx were obtained by
this method.
N‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(4‑methoxyphenyl)‑4‑
oxoazetidin‑3‑yl)‑2,6‑dimethoxybenzamide (5c)
Yield: 20 %; mp: 82-84 °C; IR (KBr) cm−1: 1677 (CO,
Amide), 1758 (CO, β-lactam), 2931 (NH); 1H-NMR
(CDCl3) δ 3.61–3.80 (OMe, s, 15H), 4.79 (H-3, dd, 1H,
J = 2.10, 8.13), 5.18 (H-2, d, 1H, J = 1.88), 6.30–8.19
(ArH, m, 10H), 8.19 (NH, d, 1H, J = 2.00); Anal. calcd. for
C27H28N2O7: C, 65.84; H, 5.73; N, 5.69. Found: C, 64.54;
H, 4.93; N, 6.12.
3‑Amino‑1‑(2,4‑dimethoxyphenyl)‑4‑(4‑nitrophenyl)
azetidin‑2‑one (4d)
Yield: 42 %; mp:138–140 °C; IR (KBr) cm−1: 1745 (CO,
β-lactam), 3290, 3379 (NH2); H-NMR (CDCl3) δ 1.99
1
(NH2, s, 2H), 3.62, 3.75 (OMe, s, 6H), 4.10 (H-3, d, 1H,
J = 1.82), 5.10 (H-4, d, 1H, J = 1.50), 6.34–8.18 (ArH, m,
7H); 13C-NMR (CDCl3) δ 55.39, 55.50 (2 OCH3), 68.74
(C-3), 70.46 (C-4), 98.61-158.72 (aromatic carbons), 168.23
(CO, β-lactam); Anal. calcd. for C17H17N3O5: C, 59.47; H,
4.99; N, 12.24. Found: C, 57.29; H, 4.48; N, 12.46.
Method B
A mixture of 2,6-dimethoxybenzoic acid (1.10 mmol),
TsCl (1.10 mmol), Et3N (1.10 mmol) and CH2Cl2
(25.00 mL) was stirred for 3 h. Then an excess amount
of Et3N (0.5 mL) and 3-amino-1-(2,4-dimethoxyphenyl)-
4-(4-nitrophenyl)azetidin-2-one 4d (1 mmol) was added
and the mixture was stirred overnight. Then the mixture
was washed with HCl 1 N, saturated sodium bicarbonate
solution, brine and dried over sodium sulfate. The solvent
was evaporated under vaccum to afford the crude amide 5d
which was then purified by column chromatography.
General procedures for the synthesis of amido
β‑lactams (5a‑c, 5d)
Method A
A mixture of oxalyl dichloride (0.17 mL, 2.00 mmol),
2,6-dimethoxybenzoic acid (1.50 mmol), CH2Cl2
(25 mL) was stirred for 30 min. Then Et3N (0.50 mL)
and the crude of 3-amino-azetidin-2-one (1.5 mmol)
from 3n were added and the mixture was stirred over-
night. Then it was washed with HCl 1 N, saturated
sodium bicarbonate solution, brine and dried over
sodium sulfate. The solvent was evaporated under vac-
cum to afford the crude amide 5a which was then puri-
fied by column chromatography.
N‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(4‑nitrophenyl)‑4‑oxoazeti‑
din‑3‑yl)‑2,6‑dimethoxybenzamide (5d)
Yield: 50 %; mp: 84–86 °C; IR (KBr) cm−1: 1688 (CO,
Amide), 1758 (CO, β-lactam), 2941 (NH); 1H-NMR
(CDCl3) δ 3.62, 3.77, 3.84 (OMe, s, 12H), 4.86 (H-3, dd,
1H, J = 1.97, 5.4), 5.44 (H-2, d, 1H, J = 1.82), 6.38–7.70
(ArH, m, 10H), 8.18 (NH, d, J = 8.65); 13C-NMR (CDCl3)
δ 55.48, 55.55, 56.07 (4 OCH3), 66.34 (C-3), 66.66 (C-4),
98.76–157.69 (aromatic carbons), 158.87 (CO, amide),
163.30 (CO, β-lactam); Anal. calcd. for C26H25N3O8: C,
61.53; H, 4.97; N, 8.28. Found: C, 59.72; H, 5.16; N, 8.05.
N‑(1‑(2,4‑Dimethoxyphenyl)‑2‑(3‑nitrophenyl)‑4‑oxoazeti‑
din‑3‑yl)‑2,6‑dimethoxybenzamide (5a)
Yield: 15 %; mp: 87–89 °C; IR (KBr) cm−1: 1672 (CO,
Amide), 1755 (CO, β-lactam), 2941 (NH); 1H-NMR
(CDCl3) δ 3.56–3.79 (OMe, s, 12H), 4.80 (H-3, dd, 1H,
J = 1.99, 5.56), 5.34 (H-2, d, 1H, J = 1.82), 6.31–8.07
(ArH, m, 10H), 8.22 (NH); Anal. calcd. for C26H25N3O8: C,
61.53; H, 4.97; N, 8.28. Found: C, 59.53; H, 4.38; N, 8.97.
Results and discussion
Schiff bases 1a‑p were prepared from dimethoxyanilines
and substituted bezaldehydes in refluxing ethanol. Then
1 3

J IRAN CHEM SOC
Yield (%)a
Yield (%)a
Table 1 Synthesis of
2-azetidinones 3a‑y
β-lactam
Structure
β-lactam
Structure
cis/trans (%)
cis/trans (%)
O
NO2
O
O
N
NO2
N
O
65 (100:0)
65 (0:100)
3a
3nb
N
O
H3CO
OCH3
OCH3
NO2
H3CO
O
N
NO2
O
O
N
80 (100:0)
N
60 (0:100)
3b
3o
O
O
H3CO
OCH3
NO2
OCH3
H3CO
O
N
O
O
O
OCH3
3cb
3db
3eb
3p
3qb
3r
N
N
79 (100:0)
45 (100:0)
75 (100:0)
75 (50:50)
60 (0:100)
85 (0:100)
O
H3CO
OCH3
OCH3
OCH3
H3CO
OCH3
OCH3
O
N
O
O
N
N
O
O
H3CO
H3CO
OCH3
OCH3
OCH3
OCH3
OCH3
O
N
O
O
O
N
N
O
H3CO
OCH3
OCH3
H3CO
O
N
O
O
O
NO2
OCH3
OCH3
N
3f
50 (100:0)
20 (100:0)
3s
3t
25 (0:100)
50 (60:40)
N
O
H3CO
OCH3
H3CO
O
NO2
N
O
OCH3
OCH3
O
O
3gb
N
N
O
H3CO
OCH3
H3CO
a mixture of Schiff base, triethylamine, substituted ace-
tic acid 2 and tosyl chloride in dry CH2Cl2 was stirred at
room temperature for 24 h to give 2-azetidinones 3a‑y
(Table 1) by the ketene–imine [2+2] cycloaddition reaction
(Staudinger reaction) (Scheme 1) [12–18].
been additionally characterized by spectral analyses. For
example, the IR spectrum of compound 3a indicated a
characteristic absorption band of a β-lactam carbonyl moi-
ety at 1751 cm−1
.
1
The H-NMR spectrum of 3a exhibited the signals of
the methoxy protons as two singlets at 3.76 and 3.80 ppm,
the β-lactam ring protons H-3 and H-4 as two doublets at
TLC monitoring confirmed the presence of the expected
new products and the structures of the cycloadducts have
1 3

J IRAN CHEM SOC
Table 1 continued
β-lactam
Structure
Yield (%)a
80 (100:0)
β-lactam
Structure
Yield (%)a
NO2
O
N
O
O
O
O
O
3hb
3ub
NO2
N
N
O
58 (100:0)
45 (0:100)
70 (0:100)
H3CO
OCH3
OCH3
H3CO
O
N
NO2
O
OCH3
N
3i
N
80 (100:0)
77 (100:0)
3v
O
O
H3CO
OCH3
OCH3
OCH3
H3CO
O
N
O
O
OCH3
N
N
3j
3w
O
OCH3
OCH3
OCH3
H3CO
H3CO
O
N
OCH3
N
O
O
O
N
65 (100:0)
50 (100:0)
80 (0:100)
80 (70:30)
3k
3lb
3xb
3y
O
OCH3
NO2
OCH3
OCH3
H3CO
H3CO
NO2
O
O
O
N
O
O
N
N
OCH3
OCH3
H3CO
H3CO
O
N
O
NO2
N
85 (0:100)
3m
O
H3CO
OCH3
6.08, 5.62 and aromatic protons as multiplets at 6.44–8.16.
Furthermore, the 13C-NMR spectrum exhibited the C-3,
and C-4 (β-lactam ring) at 82.14, 68.12 and the β-lactam
carbonyl at 163.37. The stereochemistries of these 2-aze-
tidinones were either cis or trans due to the coupling con-
stants of H-3 and H-4 of the β-lactam ring. The cis geom-
etry was assigned for the coupling constants larger than
3 Hz and the trans geometry for those lower than 3 Hz
[19]. The monocyclic β-lactams, 3a‑e, 3h, 3j‑l, 3u, were
obtained as cis isomer, whereas derivatives 3m, 3n, 3o, 3q‑
r and 3v‑x, were isolated as trans isomer and 3p, 3t and 3y
as a mixture of cis and trans isomers. On the other hand,
3-phthalimido β-lactams 3n, 3r and 3p were converted to
3-amido-2-azetidinones 5a‑c by the procedure outlined in
Scheme 2 [20].
Moreover, 3o was converted into 3-amido β-lactam 5d
as shown in Scheme 3 [21]. In these reactions, the free
3-amino azetidin-2-ones reacted with 2,6-dimethoxyben-
zoic acid in the presence of tosyl chloride as acid activator
at room temperature to afford the amido β-lactam.
Antimalarial activity of β‑lactams 3a‑x
Low to excellent antimalarial activities have been obtained
against chloroquine-resistant p. falciparum K14 strain as
outlined in Table 2 for all derivatives with IC50 varying from
1 3

J IRAN CHEM SOC
3a R1 = 3,4-DiMeOC H R2 = 2-NO C H , R3 = PhO
3m = R1 = 2,4-DiMeOC6H3, R2 = 2-NO2C6H4, R3 = PhthN
,
3
6
2
6
4
3b R1 = 3,4-DiMeOC6H3, R2 = 3-NO2C6H4, R3 = PhO
3c R1 = 3,4-DiMeOC6H3, R2 = 4-NO2C6H4, R3 = PhO
3d R1 = 2,4-DiMeOC6H3, R2 = 3,4-DiMeOC6H3, R3 = PhO
3e R1 = 3,4-DiMeOC6H3, R2 = 3,4-DiMeOC6H3, R3 = PhO
3f R1 = 2,4-DiMeOC6H3, R2 = 2-MeOC6H4, R3 = PhO
3g R1 = 2,4-DiMeOC6H3, R2 = 3-MeOC6H3, R3 = PhO
3n = R1 = 2,4-DiMeOC6H3, R2 = 3-NO2C6H4, R3 = PhthN
3o = R1 = 2,4-DiMeOC6H3, R2 = 4-NO2C6H4, R3 = PhthN
3p = R1 = 2,4-DiMeOC6H3, R2 = 2-MeOC6H4, R3 = PhthN
3q = R1 = 2,4-DiMeOC6H3, R2 = 3-MeOC6H4, R3 = PhthN
3r = R1 = 2,4-DiMeOC6H3, R2 = 4-MeOC6H4, R3 = PhthN
3s = R1 = 3,4-DiMeOC H R2 = 2-NO C H , R3 = PhthN
,
6
3
2
6
4
3h R1 = 2,4-DiMeOC6H3, R2 = 2-NO2C6H4, R3 = PhO
3i R1 = 2,4-DiMeOC6H3, R2 = 3-NO2C6H4, R3 = PhO
3j R1 = 2,4-DiMeOC6H3, R2 = 2-MeOC6H4, R3 = PhO
3k R1 = 2,4-DiMeOC6H3, R2 = 3-MeOC6H4, R3 = PhO
3l R1 = 2,4-DiMeOC6H3, R2 = 4-MeOC6H4, R3 = PhO
3t = R1 = 3,4-DiMeOC H R2 = 3-NO C H , R3 = PhthN
,
6
3
2
6
4
3u = R1 = 3,4-DiMeOC H R2 = 4-NO C H , R3 = PhthN
,
3
6
2
6
4
3v = R1 = 3,4-DiMeOC H R2 = 2-MeOC H , R3 = PhthN
,
6
3
6
4
3w = R1 = 3,4-DiMeOC H R2 = 3-MeOC H , R3 = PhthN
,
3
6
6
4
3x = R1 = 3,4-DiMeOC H R2 = 4-MeOC H , R3 = PhthN
,
3
6
6
4
3y = R1 = 3,4-DiMeOC H R2 = 4-NO C H , R3 = 3-NO PhthN
,
3
6
2
6
4
2
Scheme 1 Synthesis of β-lactams 3a‑y
OCH3
O
HO
H3CO
O
H
H2N
O
Ar
N
O
Ar
OCH3
N
Ar
H3CO
O
N2H4. H2O
MeOH, Reflux
O
N
N
N
C2O2Cl2, CH2Cl2
Et3N, rt
O
H3CO
H3CO
H3CO
OCH3
OCH3
OCH3
4a-c
3n, 3p, 3r
5a-c
5a: Ar = 3-NO2C6H4 (15%)
5b: Ar = 2-MeOC6H4 (30%)
5c: Ar = 4-MeOC6H4 (20%)
Scheme 2 Synthesis of 3-amido β-lactams 5a‑c
5 to up to 50 µM. It is also noteworthy that the best deriva-
tives 3c and 3i present a phenoxy group attached to the lac-
tam moiety, whereas their corresponding parent derivatives
3t and 3u bearing a 1H-isoindole-1,3(2H)-dione are poorly
active suggesting closely structure activity relationships.
Moreover, 3a and 3b isomers of compound 3c differ-
ing only by the position (ortho, meta) of the nitro group
are quite low active. On the other hand, parent derivative
3l of 3c remains quite interesting since the replacement of
a nitro group by a methoxy moiety led to an IC50 of 25 µM.
In conclusion, a strong influence of the structure of the con-
sidered lactam derivative on the mechanism of action is
underlined suggesting the importance of the phenoxy moi-
ety and the position of aromatic substituents. Nevertheless,
it is actually difficult to conclude on such weak differences
since the target of these derivatives remains unknown.
1 3

J IRAN CHEM SOC
NO2
NO2
NO2
OCH3
O
OH
OCH3
O
H
H3CO
H2N
O
N
N
O
methylhdrazine
CH2Cl2, rt
H3CO
O
O
N
N
N
Et3N, TsCl
CH2Cl2, rt
O
H3CO
H3CO
H3CO
OCH3
OCH3
OCH3
5d
3o
4d
Scheme 3 Synthesis of 3-amido β-lactam 5d
Table 2 Antimalarial activity of compounds 3a‑x against chloro-
quine-resistant p. falciparum K14 strain
3. E.I. Page, The chemistry of β‑lactams (Blackie Academic and
Proffessional, New York, 1992)
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5. W.H. Koster, C.M. Cimarusti, chemistry and biology of β-lactam
antibiotics, ed by R.B. Morin, M. Gorman (Academic Press:
New York, 1982)
Compound
IC50 (µM)
Compound
IC50 (µM)
3a
3b
3c
3d
3e
3f
42
3m
3n
3o
3p
3q
3r
3s
31.5
40
29
6. P. Maragni, M. Mattioli, R. Pachera, B. Tamburini, Org. Process
Res. Dev. 6, 597–605 (2002)
5.25
30
>50
36.5
46
7. H. Chambers, Emerg. Infect. Dis. 7, 178 (2001)
8. L.A. Mitscher, Antibiotics and antimicrobial agents, in Foye’s
Principles of Medicinal Chemistry, 5th edn., ed. by D.A. Wil-
liams, T.L. Lemke (Lippincott Williams & Wilkins, Philadelphia,
2002)
9. M. Gladwin, B. Trattler, Clinical Microbiology Made Ridicu‑
lously Simple, 3rd edn. (MedMaster, Inc., Miami, 2004)
10. M. Akkurt, A. Jarrahpour, M. Aye, M. Gencaslan O. Buyukgun-
gor, Acta Crystallogr E64, 2175–2176 (2008)
36.5
24.11
26.71
21
>50
45
3g
3h
3i
3t
>50
>50
28
13.25
50
3u
3v
3w
3x
3j
11. M. Akkurt, A. Jarrahpour, M. Aye, M. Gencaslan O. Buyukgun-
gor, Acta Crystallogr E64, 2087 (2008)
3k
3l
28.59
25
47
>50
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116, 11509 (2000)
In conclusion, these new β-lactam derivatives are eas-
ily prepared and appear as new potent antimalarial agents.
Works are now under process to investigate their biological
mechanism of action and will be reported in due course.
16. L.S. Hegedus, J. Montgomery, Y. Narukawa, D.C. Snustad, J.
Am. Chem. Soc. 113, 5784 (1991)
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20. M. Sierra, M. Fernandez, M. Mancheno, L. Casarrubio, M. Gal-
lego, Tetrahedron 64, 9592 (2008)
Acknowledgments The authors thank the Shiraz University
Research Council for financial support (Grant No. 93-GR-SC-23).
21. M. Jayaraman, V. Srirajan, A.R.A.S. Deshmukh, B.M. Bhawal,
Tetrahedron 52, 3741 (1996)
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1 3