Amino acid derivatives, VIII [1]: Synthesis and antimicrobial evaluation of α-amino acid esters bearing an indole side chain

Article abstract of DOI:10.1007/s00706-008-0891-7

A series of peptide and dipeptide derivatives conjugated with an indole residue were synthesized. The prepared compounds were tested for antimicrobial activity against two different bacterial and one antifungal species displaying different degrees of antimicrobial activities or inhibitory actions.

Full text of DOI:10.1007/s00706-008-0891-7

Monatsh Chem 139, 1095–1101 (2008)
DOI 10.1007/s00706-008-0891-7
Printed in The Netherlands
Amino acid derivatives, VIII [1]: synthesis and antimicrobial
evaluation of a-amino acid esters bearing an indole side chain
Adel A.-H. Abdel-Rahman1, Wael A. El-Sayed2, Hamed M. Abdel-Bary1,
Ahmed E.-S. Abdel-Megied1, Emad M. I. Morcy1
1
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt
2
National Research Centre, Photochemistry Department, Cairo, Egypt
Received 21 December 2007; Accepted 10 January 2008; Published online 20 February 2008
# Springer-Verlag 2008
Abstract A series of peptide and dipeptide derivatives
conjugated with an indole residue were synthesized.
The prepared compounds were tested for antimicro-
bial activity against two different bacterial and one
antifungal species displaying different degrees of an-
timicrobial activities or inhibitory actions.
connection with synthesis of new ꢀ-amino acid deriv-
atives [12] and due to the pharmacological proper-
ties of indoles and amino acid derivatives we were
prompted to prepare new indole bearing amino acid
derivatives to study their antimicrobial activity.
Keywords Indole derivatives; Amino acids; Dipeptides; An-
timicrobial activity.
Introduction
Indole derivatives are of great significance because
of their occurrence in Nature as part of the structure
of a large number of alkaloids [2–4] and their wide-
ranging biological activity [5, 6], and for this reason
indole synthesis is a very active field [7, 8]. On the
other hand, several ꢀ-amino acids conjugated hetero-
cyles reported as potential antitumor agents, such as
4-toluenesulfonylureido derivatives of amines, ami-
no acids, dipeptides [9], and 2-(4-aminophenyl)ben-
zothiazoles [10]. Some alkylating agents bearing
amino acid residues showed high cytotoxic activity
against various cancer cell lines, such as melphalan
(L-phenylalanine Mustard hydrochloride) [11]. In
Results and discussion
Chemistry
Indole derivatives 1a–1c were treated with ethyl
chloroacetate in dry acetone containing anhydrous
K2CO3 at reflux temperature to afford 1-(ethoxycar-
bonylmethyl)-1H-indoles 2a–2c in 74–80% yields.
1
The H NMR spectra showed a triplet at ꢁ ¼ 1.21–
1.28 ppm and a quartet at ꢁ ¼ 4.15–4.24 ppm cor-
responds to OEt. The singlet at ꢁ ¼ 5.11–5.22 ppm
corresponds to N1-CH2, while the signals of H-3 and
H-2 appeared as two doublets at ꢁ ¼ 6.40–6.45 and
6.90–6.99 ppm. Nitration of 2a–2c using acetyl ni-
trate afforded the corresponding 3-nitroindole de-
Correspondence: Adel A.-H. Abdel-Rahman, Department of
Chemistry, Faculty of Science, Menoufia University, Shebin
El-Koam, Egypt. E-mail: adelnassar63@hotmail.com
1
rivatives 3a–3c in 94–98% yields. The H NMR
spectra showed a singlet at ꢁ ¼ 7.70–7.75 ppm

1096
A. A.-H. Abdel-Rahman et al.
corresponding to H-2. Treatment of 2a–2c or 3a–3c
with hydrazine hydrate in ethanol gave the corre-
sponding hydrazide derivatives 4a–4c in 92–95%
or 5a–5c in 91–94% yields. These hydrazides were
selected as starting materials for the coupling reac-
tion with the appropriate acylated amino acides, via
the azide-coupling method [13]. Thus, treatment of
4a–4c or 5a–5c at ꢀ5ꢁC in AcOH and 1 N HCl with
Scheme 1
Scheme 2

Amino acid derivatives, VIII
1097
NaNO2 afforded the inseparable azide derivative.
The yellow syrupy azide compound was then treat-
ed, in situ, with the appropriate amino acid methyl
esters in ethyl acetate containing Et3N at 0ꢁC to give,
after neutralization, the desired peptides 6–14 in 73–
79% or 15–23 in 70–78% yields. The structures of
Antimicrobial activity
New ꢀ-amino acid derivatives bearing an indole side
chain were preliminarily evaluated for their in vitro
antibacterial activity against two representative types
of bacteria, Staphylococcus aureus as Gram-positive
bacteria and Escherichia coli as Gram-negative bacte-
ria. The last compounds were also evaluated for their
in vitro antifungal activity against C. albicans. Their
inhibition zones using the agar cup diffusion technique
[14, 15] were measured. Cefotaxim was used as an-
tibacterial reference, while nystatin was used as anti-
fungal reference. The highest degrees of inhibition
were recorded for compounds 10, 11, 13, 16, 18–20,
27, and 29–31 followed by 9, 12, 14, 21–23, 26, and
28, while the lowest degree of inhibition was recorded
for compounds 6–8, 15, and 17 (Table 1).
1
6–19 were assigned from their H NMR and mass
spectra (Scheme 1).
Treating of 9 or 18 with N2H4 ꢂ H2O in ethanol
at reflux temperature afforded the corresponding
hydrazides 24 or 25 in 91–93% yields. Treatment
of 24 or 25 at ꢀ5ꢁC in AcOH and 1 N HCl with
NaNO2 afforded the inseparable azide derivatives.
The yellow syrupy azide compounds were treated,
as mentioned above, with the appropriate amino acid
methyl esters in ethyl acetate containing Et3N at 0ꢁC
to afford 26–28 in 72–75% and 29–31 in 70–72%
yields. The structures of the dipeptide derivatives
1
Conclusions
were confirmed by their H NMR and mass spectra
(Scheme 2).
New ꢀ-amino acid derivatives bearing an indole side
chain were synthesized in order to increase the num-
ber of tested compounds screened for antimicrobial
activity. The data recorded in Table 1 revealed that
the 6-haloindoles as well as 6-halo-3-nitroindoles
were the most active compounds.
Table 1 Antimicrobial activity of the newly synthesized ꢀ-
amino acid derivatives 6–23 and 26–31
Compound No.
S. aureus
E. coli
C. albicans
DMF
Cefotaxim
Nystatin
6
7
8
–
þ
þ
þ þ
þ
–
–
–
þ
Experimental
þ
þ
þ
þ þ
þ
þ
General
þ
þ
þ
Melting points were determined using a Kofler block in-
strument. TLC was performed on plastic plates Silica Gel
60 F254 (E. Merck, layer thickness 0.2 mm). NMR spectra
were recorded on a Bruker AC 250 FT NMR spectrometer
at 250MHz for 1H NMR with TMS as an internal standard. ES
mass spectra were obtained from an Esquire 3000plus iontrap
mass spectrometer from Bruker Daltonics. The microanalyses
were performed at the microanalytical unit, Cairo University,
Egypt, and were found to agree favourably with the calculated
values. Antimicrobial activity of the synthesized compounds
was conducted at the Botany Department, Faculty of Science,
Menoufia University, Shebin El-Koam, Egypt.
9
þ þ þ
þ þ þþ
þ þ þþ
þ þ þ
þ þ þþ
þ þ þ
þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ
þ þ
þ þ
þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
26
27
28
29
30
31
þ
þ þ
þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ þ
þ
þ þ þþ
þ þ
þ þ þþ
þ þ þþ
þ þ þþ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þþ
þ þ þ
þ þ þþ
þ þ þþ
þ þ þþ
General procedure for the preparation of 1-(ethoxycarbonyl-
methyl)-1H-indoles 2a–2c
þ
þ
A mixture of 1a–1c (0.1mol), 14.7g ethyl chloroacetate
(0.12 mol), and 13.8g anhydrous K2CO3 (0.1mol) in 36cm3
dry acetone was refluxed for 5 h (TLC). The solvent was
removed in vacuo and the residue was diluted with H2O and
extracted with CH2Cl2 (3ꢃ30cm). The combined organic
layers were dried (Na2SO4) and the solvent was evaporated.
The residue was purified by silica gel column chromatography
using (petroleum ether:EtOAc ¼ 7:1) to afford 12.24 g 2 (60%)
and 6.12g 3 (30%).
þ
þ
þ
þ
þ
þ
–: no effect, þ: low effect, þ þ: moderate effect, þ þ þ: high
effect, and þ þ þþ: complete effect

1098
A. A.-H. Abdel-Rahman et al.
H-2), 8.19 (d, J ¼ 7.5 H-5) ppm; MS (ESI): m=z ¼ 305
[Mþ þ Na].
Ethyl 2-(1H-indol-1-yl)acetate (2a, C12H13NO2)
White powder (80%); mp 145–147ꢁC; 1H NMR (CDCl3,
250 MHz): ꢁ ¼ 1.21 (t, J ¼ 6.1 Hz, CH3CH2O), 4.15 (q, J ¼
6.1 Hz, CH3CH2O), 5.11 (s, N1-CH2), 6.40 (d, J ¼ 7.0 Hz,
H-3), 6.90 (d, J ¼ 7.0 Hz, H-2), 7.48–7.66 (m, Ar–H) ppm;
MS (ESI): m=z ¼ 226 [Mþ þ Na].
General procedure for the preparation of 1-acetylhydrazine-
1H-indoles 4a–4c and 5a–5c
A mixture of 2a–2c or 3a–3c (10 mmol) and 1.25 g
N2H4 ꢂ H2O (25 mmol) in 30cm3 ethanol was heated under
reflux for 2 h. The excess of ethanol was removed under re-
duced pressure and the resulting precipitate was filtered off,
washed with ethanol, and recrystallized from ethanol to give 4
(93%) and 5 (90%).
Ethyl 2-(6-bromo-1H-indol-1-yl)acetate (2b, C12H12BrNO2)
White powder (78%); mp 188–189ꢁC; 1H NMR (CDCl3,
250 MHz): ꢁ ¼ 1.27 (t, J ¼ 6.1 Hz, CH3CH2O), 4.20 (q, J ¼
6.1 Hz, CH3CH2O), 5.18 (s, N1-CH2), 6.44 (d, J ¼ 7.0 Hz,
H-3), 6.97 (d, J ¼ 7.0 Hz, H-2), 7.00 (d, J ¼ 7.5 Hz, H-4),
7.25 (d, J ¼ 7.5 Hz, H-5), 7.66 (s, H-7) ppm; MS (ESI):
m=z ¼ 304=306 [Mþ þ Na].
2-(lH-Indol-l-yl)acetohydrazide (4a, C10H11N3O)
White powder (95%); mp 220–222ꢁC; 1H NMR (DMSO-
d6, 250 MHz): ꢁ ¼ 4.20 (br, s, NHNH2), 5.06 (s, N1-CH2),
6.41 (d, J ¼ 7.0 Hz, H-3), 7.42 (d, J ¼ 7.0 Hz, H-2), 7.70–
7.94 (m, Ar–H), 9.50 (br, s, NHNH2) ppm; MS (ESI):
m=z ¼ 212 [Mþ þ Na].
Ethyl 2-(6-chloro-1H-indol-1-yl)acetate (2c, C12H12ClNO2)
White powder (74%); mp 122–124ꢁC; 1H NMR (CDCl3,
250 MHz): ꢁ ¼ 1.28 (t, J ¼ 6.1 Hz, CH3CH2O), 4.24 (q, J ¼
6.1 Hz, CH3CH2O), 5.22 (s, N1-CH2), 6.45 (d, J ¼ 7.0 Hz,
H-3), 6.99 (d, J ¼ 7.0 Hz, H-2), 7.09 (d, J ¼ 7.5 Hz, H-4),
7.33 (d, J ¼ 7.5 Hz, H-5), 7.71 (s, H-7) ppm; MS (ESI):
m=z ¼ 260 [Mþ þ Na].
2-(6-Bromo-1H-indol-1-yl)acetohydrazide
(4b, C10H10BrN3O)
Pale yellow powder (93%); mp 187–189ꢁC; 1H NMR
(DMSO-d6, 250MHz): ꢁ ¼ 4.66 (br, s, NHNH2), 5.14 (s, N1-
CH2), 6.45 (d, J ¼ 7.0 Hz, H-3), 7.08 (d, J ¼ 7.5 Hz, H-4), 7.19
(d, J ¼ 7.5Hz, H-5), 7.53 (d, J ¼ 7.0 Hz, H-2), 7.66 (s, H-7),
9.45 (br, s, NHNH2) ppm; MS (ESI): m=z ¼ 290=292
[Mþ þ Na].
General procedure for the preparation of 1-(ethoxycarbonyl-
methyl)-3-nitro-1H-indoles 3a–3c
Acetyl nitrate was generated by the dropwise addition of
1.35cm3 neat yellow 90% HNO3 (30 mmol) to 20cm3 cooled
(0ꢁC) Ac2O followed by standing at room temperature for
10min and was used immediately. To a stirred solution of
2a–2c (1mmol) in 2 cm3 Ac2O at ꢀ70ꢁC was added a solution
of the acetyl nitrate dropwise via addition funnel over 30min.
The mixture was then allowed to warm to room temperature
with stirring overnight. The reaction mixture was poured on
crushed ice and then extracted with 100 cm3 CH2C12. The
solvent was dried over Na2SO4, evaporated, and coevaporated
with toluene to afford a yellow solid which was purified by
column chromatography (EtOAc:n-hexane¼ 1:9) to give 3a–
3c in 94–98% yields.
2-(6-Chloro-1H-indol-1-yl)acetohydrazide
(4c, C10H10ClN3O)
1
White powder (92%); mp 236–238ꢁC; H NMR (DMSO-d6,
250 MHz): ꢁ ¼ 4.43 (br, s, NHNH2), 5.10 (s, N1-CH2), 6.75 (d,
J ¼ 7.0Hz, H-3), 7.02 (d, J ¼ 7.5 Hz, H-4), 7.14 (d, J ¼ 7.5 Hz,
H-5), 7.55 (s, H-7), 7.73 (d, J ¼ 7.0 Hz, H-2), 9.49 (br, s,
NHNH2) ppm; MS (ESI): m=z ¼ 246 [Mþ þ Na].
2-(3-Nitro-1H-indol-1-yl)acetohydrazide (5a, C10H10N4O3)
Pale yellow powder (94%); mp 163–165ꢁC; 1H NMR
(DMSO-d6, 250MHz): ꢁ ¼ 4.35 (br, s, NHNH2), 4.99 (s, N1-
CH2), 7.30–7.50 (m, Ar–H), 7.72 (s, H-2), 9.20 (br, s,
NHNH2) ppm; MS (ESI): m=z ¼ 257 [Mþ þ Na].
Ethyl 2-(3-nitro-1H-indol-1-yl)acetate (3a, C12H12N2O4)
Yellow foam (98%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.25 (t,
J ¼ 6.1 Hz, CH3CH2O), 4.12 (q, J ¼ 6.1 Hz, CH3CH2O), 5.00
(s, N1-CH2), 7.34–7.40 (m, Ar–H), 7.70 (s, H-2), 7.90–7.97
(m, Ar–H) ppm; MS (ESI): m=z ¼ 271 [Mþ þ Na].
2-(6-Bromo-3-nitro-1H-indol-1-yl)acetohydrazide
(5b, C10H9BrN4O3)
Pale yellow powder (93%); mp 199–201ꢁC; 1H NMR
(DMSO-d6, 250MHz): ꢁ ¼ 4.60 (br, s, NHNH2), 5.06 (s, N1-
CH2), 7.55 (m, Ar–H), 7.77 (s, H-2), 7.96 (s, H-7), 9.32 (br, s,
NHNH2) ppm; MS (ESI): m=z ¼ 335=337 [Mþ þ Na].
Ethyl 2-(6-bromo-3-nitro-1H-indol-1-yl)acetate
(3b, C12H11BrN2O4)
Yellow foam (95%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.27 (t,
J ¼ 6.1 Hz, CH3CH2O), 4.16 (q, J ¼ 6.1 Hz, CH3CH2O), 4.98
(s, N1-CH2), 7.60–7.69 (m, Ar–H), 7.75 (s, H-2), 8.05 (s, H-7)
ppm; MS (ESI): m=z ¼ 349=351 [Mþ þ Na].
2-(6-Chloro-3-nitro-1H-indol-1-yl)acetohydrazide
(5c, C10H9ClN4O3)
Pale yellow powder (91%); mp 229–231ꢁC; 1H NMR
(DMSO-d6, 250MHz): ꢁ ¼ 4.50 (br, s, NHNH2), 5.02 (s, N1-
CH2), 7.65 (d, J ¼ 7.5Hz, H-4), 7.90 (s, H-7), 8.00 (d,
J ¼ 7.5Hz, H-5), 8.06 (s, H-2), 9.45 (br, s, NHNH2) ppm;
MS (ESI): m=z ¼ 291 [Mþ þ Na].
Ethyl 2-(6-chloro-3-nitro-1H-indol-1-yl)acetate
(3c, C12H11ClN2O4)
Yellow foam (94%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.26 (t,
J ¼ 6.1 Hz, CH3CH2O), 4.13 (q, J ¼ 6.1 Hz, CH3CH2O), 4.99
(s, N1-CH2), 7.75 (d, J ¼ 7.5 Hz, H-4), 7.98 (s, H-7), 8.06 (s,

Amino acid derivatives, VIII
1099
General procedure for the preparation of N1-indole bearing
amino acid esters 6–23
J ¼ 7.0Hz, H-2), 7.68 (s, H-7), 8.33 (br, s, NH) ppm; MS
(ESI): m=z ¼ 361=363 [Mþ þ Na].
A solution of 1.90g 4 or 5 (4mmol) in 30 cm3 HOAc, 15 cm3
1 N HCl, and 125 cm3 H2O was cooled in an ice-bath (ꢀ5ꢁC).
Sodium nitrite (4.35 g, 63 mmol) in 15 cm3 cold H2O was
added with stirring. After stirring at ꢀ5ꢁC for 15 min, the
yellow syrup was formed. The azide was taken in 150 cm3
cold ethyl acetate, washed with 150 cm3 NaHCO3 (3%),
150 cm3 H2O, and dried (Na2SO4). A solution of the appropri-
ate amino acid methyl ester hydrochloride (4.5mmol) in
100 cm3 ethyl acetate containing 1.0cm3 Et3N was stirred at
0ꢁC for 20 min, filtered, and the filtrate was added to the azide
solution. The mixture was kept at ꢀ5ꢁC for 12h, then at room
temperature for another 12 h, followed by washing with
150 cm3 0.5 N HC1, 150 cm3 NaHCO3 (3%), 150 cm3 H2O,
and dried (Na2SO4). The filtrate was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography using petroleum ether:EtOAc¼ 7:1 to afford
6–14 in 73–79% or 15–23 in 70–79% yields.
(S)-Methyl 2-[2-(6-bromo-1H-indol-1-yl)acetamido]-3-methyl-
butanoate (11, C16H19BrN2O3)
Pale yellow foam (73%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 0.96 (dd, J ¼ 1.9, 7.2 Hz, 2ꢃCH3), 2.30–2.40 (m, CH),
3.50 (s, OCH3), 4.26–4.38 (m, CH), 5.48 (s, N1-CH2), 6.49 (d,
J ¼ 7.0Hz, H-3), 7.06 (d, J ¼ 7.5 Hz, H-4), 7.13 (d, J ¼ 7.5 Hz,
H-5), 7.58 (d, J ¼ 7.0 Hz, H-2), 7.69 (s, H-7), 8.37 (br, s, NH)
ppm; MS (ESI): m=z ¼ 389=391 [Mþ þ Na].
Methyl 2-[2-(6-chloro-1H-indol-1-yl)acetamido]acetate
(12, C13H13ClN2O3)
Colorless syrup (75%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.50
(s, OCH3), 4.11 (s, CH2), 5.47 (s, Nl-CH2), 6.79 (d, J ¼ 7.0 Hz,
H-3), 7.09 (d, J ¼ 7.5 Hz, H-4), 7.17 (d, J ¼ 7.5 Hz, H-5), 7.50
(s, H-7), 7.73 (d, J ¼ 7.0Hz, H-2), 8.40 (br, s, NH) ppm; MS
(ESI): m=z ¼ 303 [Mþ þ Na].
Methyl 2-[2-(1H-indol-1 -yl)acetamido]acetate
(6, C13H14N2O3)
(S)-Methyl 2-[2-(6-chloro-1H-indol-1-yl)acetamido]-
propanoate (13, C14H15ClN2O3)
White foam (77%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.60 (s,
OCH3), 4.00 (s, CH2), 5.43 (s, N1-CH2), 6.53 (d, J ¼ 7.0 Hz,
H-3), 7.59 (d, J ¼ 7.0 Hz, H-2), 7.74–7.81 (m, Ar–H), 8.40
(br, s, NH) ppm; MS (ESI): m=z ¼ 269 [Mþ þ Na].
Colorless syrup (74%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.53
(d, J ¼ 5.0 Hz, CH3), 3.53 (s, OCH3), 4.57 (q, J ¼ 5.0 Hz, CH),
5.50 (s, N1-CH2), 6.74 (d, J ¼ 7.0 Hz, H-3), 7.06 (d,
J ¼ 7.5Hz, H-4), 7.14 (d, J ¼ 7.5Hz, H-5), 7.53 (s, H-7),
7.76 (d, J ¼ 7.0 Hz, H-2), 8.42 (br, s, NH) ppm; MS (ESI):
m=z ¼ 217 [Mþ þ Na].
(S)-Methyl 2-[2-(1H-indol-1-yl)acetamido]propanoate
(7, C14H16N2O3)
1
White foam (79%); H NMR (CDCl3, 50 MHz): ꢁ ¼ 1.49 (d,
(S)-Methyl 2-[2-(6-chloro-1H-indol-1-yl)acetamido]-3-methyl-
butanoate (14, C16H19ClN2O3)
J ¼ 5.0 Hz, CH3), 3.50 (s, OCH3), 4.50 (q, J ¼ 5.0 Hz, CH),
5.50 (s, N1-CH2), 6.60 (d, J ¼ 7.0Hz, H-3), 7.55 (d,
J ¼ 7.0 Hz, H-2), 7.70–7.85 (m, Ar–H), 8.40 (br, s, NH)
ppm; (MS (ESI): m=z ¼ 283 [Mþ þ Na].
Colorless syrup (73%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.99
(dd, J ¼ 1.9, 7.2 Hz, 2ꢃCH3), 2.30–2.44 (m, CH), 3.55
(s, OCH3), 4.30–4.46 (m, CH), 5.45 (s, Nl-CH2), 6.70 (d,
J ¼ 7.0Hz, H-3), 7.03 (d, J ¼ 7.5 Hz, H-4), 7.19 (d,
J ¼ 7.5Hz, H-5), 7.57 (s, H-7), 7.80 (d, J ¼ 7.0 Hz, H-2),
8.44 (br, s, NH) ppm; MS (ESI): m=z ¼ 345 [Mþ þ Na].
(S)-Methyl 2-[2-(1H-indol-1 -yl)acetamido]-3-
methylbutanoate (8, C16H20N2O3)
White foam (78%); !H NMR (CDC13, 250 MHz): ꢁ ¼ 0.99 (dd,
J ¼ 1.9, 7.2 Hz, 2ꢃCH3), 2.30–2.37 (m, CH), 3.60 (s, OCH3),
4.30–4.40 (m, CH), 5.51 (s, N1-CH2), 6.63 (d, J ¼ 7.0 Hz, H-3),
7.52 (d, J ¼ 7.0 Hz, H-2), 7.69–7.80 (m, Ar–H), 8.40 (br, s,
NH) ppm; MS (ESI): m=z ¼ 311 [Mþ þ Na].
Methyl 2-[2-(3-nitro-1H-indol-1-yl)acetamido]acetate
(15, C13H13N3O5)
Pale yellow foam (78%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 3.62 (s, OCH3), 4.06 (s, CH2), 5.48 (s, N1-CH2), 7.30–
7.48 (m, Ar–H), 7.70 (s, H-2), 8.30 (br, s, NH) ppm; MS
(ESI): m=z ¼ 314 [Mþ þ Na].
Methyl 2-[2-(6-bromo-1H-indol-1-yl)acetamido]acetate
(9, C13H13BrN2O3)
Pale yellow foam (75%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 3.57 (s, OCH3), 4.09 (s, CH2), 5.55 (s, N1-CH2), 6.52 (d,
J ¼ 7.0 Hz, H-3), 7.00 (d, J ¼ 7.5 Hz, H-4), 7.22 (d, J ¼ 7.5 Hz,
H-5), 7.48 (d, J ¼ 7.0 Hz, H-2), 7.60 (s, H-7), 8.30 (br, s, NH)
ppm; MS (ESI): m=z ¼ 347=349 [Mþ þ Na].
(S)-Methyl 2-[2-(3-nitro-1H-indol-1-yl)acetamido]-
propanoate (16, C14H15N3O5)
Pale yellow foam (78%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 1.52 (d, J ¼ 5.0 Hz, CH3), 3.56 (s, OCH3), 4.50 (q,
J ¼ 5.0Hz, CH), 5.50 (s, N1-CH2), 7.30–7.53 (m, Ar–H),
7.77 (s, H-2), 8.37 (br, s, NH) ppm; MS (ESI): m=z ¼ 328
[Mþ þ Na].
(S)-Methyl 2-[2-(6-bromo-1H-indol-1-yl)acetamido]-
propanoate (10, C14H15BrN2O3)
Pale yellow foam (74%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 1.45 (d, J ¼ 5.0 Hz, CH3), 3.42 (s, OCH3), 4.39 (q,
J ¼ 5.0 Hz, CH), 5.44 (s, N1-CH2), 6.52 (d, J ¼ 7.0 Hz, H-3),
7.11 (d, J ¼ 7.5 Hz, H-4), 7.16 (d, J ¼ 7.5 Hz, H-5), 7.55 (d,
(S)-Methyl 2-[2-(3-nitro-1H-indol-1-yl)acetamido]-3-methyl-
butanoate (17, C16H19N3O5)
Pale yellow foam (77%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 0.96 (dd, J ¼ 1.9, 7.2 Hz, 2ꢃCH3), 2.34–2.44 (m, CH),

1100
A. A.-H. Abdel-Rahman et al.
3.50 (s, OCH3), 4.30–4.38 (m, CH), 5.50 (s, N1-CH2), 7.30–
7.45 (m, Ar–H), 7.71 (s, H-2), 8.36 (br, s, NH) ppm; MS
(ESI): m=z ¼ 356 [Mþ þ Na].
and the resulting precipitate was filtered off and recrystallized
from EtOH to give 24 and 25 in 91–93% yields.
2-(6-Bromo-1H-indol-1-yl)-N-(2-hydrazinyl-2-oxoethyl)-
Methyl 2-[2-(6-bromo-3-nitro-1H-indol-1-yl)acetamido]-
acetate (18, C13H12BrN3O5)
acetamide (24, C12H13BrN4O2)
1
White powder (93%); mp 188–189ꢁC; H NMR (DMSO-d6,
Pale yellow syrup (76%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 3.58 (s, OCH3), 4.00 (s, CH2), 5.47 (s, N1-CH2), 7.55
(m, Ar–H), 7.77 (s, H-2), 7.97 (s, H-7), 8.34 (br, s, NH)
ppm; MS (ESI): m=z ¼ 392=394 [Mþ þ Na].
250 MHz): ꢁ ¼ 3.53 (s, CH2), 4.90 (br, s, NHNH2), 5.22 (s, N1-
CH2), 7.50–7.55 (m, Ar–H), 7.72–7.79 (m, Ar–H), 7.92 (s, H-
7), 9.32 (br, s, NHNH2) ppm; MS (ESI): m=z ¼ 347=349
[Mþ þ Na].
(S)-Methyl 2-[2-(6-bromo-3-nitro-1H-indol-1-yl)-
2-(6-Bromo-3-nitro-1H-indol-1-yl)-N-(2-hydrazinyl-2-
acetamido]propanoate (19, C14H14BrN3O5)
1
oxoethyl)acetamide (25, C12H12BrN5O4)
1
White powder (91%); mp 212–214ꢁC; H NMR (DMSO-d6,
Pale yellow foam (75%); H NMR (CDCl3, ꢁ ¼ 250 MHz):
250 MHz): ꢁ ¼ 3.57 (s, CH2), 5.03 (br, s, NHNH2), 5.19 (s, N1-
CH2), 7.45–7.59 (m, Ar–H), 7.78 (s, H-2), 7.99 (s, H-7), 9.40
(br, s, NHNH2) ppm; MS (ESI): m=z ¼ 392=394 [Mþ þ Na].
ꢁ ¼ 1.45 (d, J ¼ 5.0 Hz, CH3), 3.48 (s, OCH3), 4.52 (q,
J ¼ 5.0 Hz, CH), 5.60 (s, N1-CH2), 7.57 (m, Ar–H), 7.79 (s,
H-2), 7.96 (s, H-7), 8.32 (br, s, NH) ppm; MS (ESI):
m=z ¼ 406=408 [Mþ þ Na].
General procedure for the preparation of dipeptides 26–31
A solution of 24 or 25 (1 mmol) in 7 cm3 HOAc, 4 cm3 1 N
HCl, and 30cm3 H2O was cooled in an ice-bath (ꢀ5ꢁC).
Sodium nitrite (1g, 14.31 mmol) in 4 cm cold H2O was added
with stirring. After stirring at ꢀ5ꢁC for 15min, the yellow
syrup was formed. The azide was taken in 30cm3 cold ethyl
acetate, washed with 30cm3 NaHCO3 (3%), 30 cm3 H2O, and
dried (Na2SO4). A solution of the appropriate amino acid
methyl ester hydrochloride (1mmol) in 22 cm3 ethyl acetate
containing 0.3 cm3 of Et3N was stirred at 0ꢁC for 20 min,
filtered, and the filtrate was added to the azide solution. The
mixture was kept at ꢀ5ꢁC for 12h, then at room temperature
for another 12h, followed by washing with 30cm3 0.5 N HCl,
30cm3 NaHCO3 (3%), 30cm3 H2O, and dried (Na2SO4). The
filtrate was evaporated under reduced pressure, and the residue
was purified by silica gel column chromatography using pe-
troleum ether:EtOAc¼ 5:1 to afford 26–28 in 75–78% and
29–31 in 70–71% yields.
(S)-Methyl 2-[2-(6-bromo-3-nitro-1H-indol-1-yl)acetamido]-
3-methylbutanoate (20, C16H18BrN3O5)
Pale yellow foam (74%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 0.97 (dd, J ¼ 1.9, 7.2 Hz, 2ꢃCH3), 2.30–2.39 (m, CH),
3.60 (s, OCH3), 4.30–4.40 (m, CH), 5.50 (s, N1-CH2), 7.50
(m, Ar–H), 7.75 (s, H-2), 7.97 (s, H-7), 8.30 (br, s, NH) ppm;
MS (ESI): m=z ¼ 434=436 [Mþ þ Na].
Methyl 2-[2-(6-chloro-3-nitro-1H-indol-1-yl)acetamido]-
acetate (21, C13H12ClN3O5)
Colorless syrup (73%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.50
(s, OCH3), 3.98 (s, CH2), 5.42 (s, N1-CH2), 7.60 (d,
J ¼ 7.5 Hz, H-4), 7.90 (s, H-7), 8.02 (d, J ¼ 7.5Hz, H-5),
8.11 (s, H-2), 8.35 (br, s, NH) ppm; MS (ESI): m=z ¼ 348
[Mþ þ Na].
(S)-Methyl 2-[2-(6-chloro-3-nitro-1H-indol-1-yl)-
acetamido]propanoate (22, C14H14ClN3O5)
Colorless syrup (72%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.43
(d, J ¼ 5.0 Hz, CH3), 3.50 (s, OCH3), 4.47 (q, J ¼ 5.0 Hz, CH),
5.56 (s, N1-CH2), 7.64 (d, J ¼ 7.5 Hz, H-4), 7.80 (s, H-7), 8.06
(d, J ¼ 7.5 Hz, H-5), 8.09 (s, H-2), 8.30 (br, s, NH) ppm; MS
(ESI): m=z ¼ 362 [Mþ þ Na].
Methyl 2-{2-[2-(6-bromo-1H-indol-1-yl)acetamido]-
acetamido}acetate (26, C15H16BrN3O4)
Pale yellow foam (75%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 3.50 (s, OCH3), 3.60 (s, CH2), 3.80 (s, CH2), 5.10 (s,
N1-CH2), 7.50–7.60 (m, Ar–H), 7.70–7.77 (m, Ar–H), 7.90
(s, H-7), 8.67 (br, s, NH) ppm; MS (ESI): m=z ¼ 404=406
[Mþ þ Na].
(S)-Methyl 2-[2-(6-chloro-3-nitro-1H-indol-1-yl)acetamido]-
3-methylbutanoate (23, C16H18ClN3O5)
Colorless syrup (70%); lH NMR (CDC13, 250 MHz): ꢁ ¼ 0.98
(dd, J ¼ 1.9, 7.2 Hz, 2ꢃCH3), 2.33–2.42 (m, CH), 3.63 (s,
OCH3), 4.30–4.44 (m, CH), 5.55 (s, N1-CH2), 7.63 (d,
J ¼ 7.5 Hz, H-4), 7.86 (s, H-7), 8.02 (d, J ¼ 7.5Hz, H-5),
8.11 (s, H-2), 8.42 (br, s, NH) ppm; MS (ESI): m=z ¼ 390
[Mþ þ Na].
(S)-Methyl 2-{2-[2-(6-bromo-1H-indol-1-yl)acetamido]-
acetamido}propanoate (27, C16H18BrN3O4)
Pale yellow foam (72%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 1.37 (d, J ¼ 5.0 Hz, CH3), 3.60 (s, CH2), 3.70 (s, OCH3),
4.50 (q, J ¼ 5.0 Hz, CH), 5.22 (s, N1-CH2), 7.50–7.56 (m, Ar–
H), 7.72–7.79 (m, Ar–H), 7.88 (s, H-7), 9.01 (br, s, NH) ppm;
MS (ESI): m=z ¼ 418=420 [Mþ þ Na].
General procedure for the preparation of the hydrazides 24
and 25
A mixture of 9 or 18 (5mmol) and 0.63 g N2H4 ꢂ H2O
(12.5mmol) in 15 cm3 EtOH was heated under reflux for
4 h. The excess of EtOH was removed under reduced pressure
(S)-Methyl 2-{2-[2-(6-bromo-1H-indol-1-yl)acetamido]-
acetamido}-3-methylbutanoate (28, C18H22BrN3O4)
Pale yellow foam (72%); 1H NMR (CDCl3, 250 MHz):
ꢁ ¼ 0.92 (dd, J ¼ 1.9, 7.3 Hz, 2ꢃCH3), 2.25–2.38 (m, CH),

Amino acid derivatives, VIII
1101
3.55 (s, OCH3), 3.70 (s, CH2), 3.77 (s, CH2), 4.35–4.49 (m,
CH), 5.19 (s, N1-CH2), 7.50–7.55 (m, Ar–H), 7.70–7.80 (m,
Ar–H), 7.90 (s, H-7), 8.89 (br, s, NH) ppm; MS (ESI):
m=z ¼ 446=448 [Mþ þ Na].
4. Lounasmaa M, Tolvanen A (2000) Nat Prod Rep
17:175
5. Gribble GW (1995) Five-membered rings with one het-
eroatom and fused carbocyclic derivatives. In: Bird CW,
Katrizky AR, Rees CW, Scriven EFV (eds) Comprehen-
sive heterocyclic chemistry: Vol. 2, 2nd edn, Pergamon
Press, Oxford, pp 207
´
6. Sridharan V, Perumal S, Avendan˜o C, Menendez JC
(2005) Synlett 1:91
´
7. Tois T, Franzen R, Koskinen A (2003) Tetrahedron
59:5395
8. Gribble GW (2000) J Chem Soc Perkin Trans 1, 1045
9. Mastrolorenzo A, Scozzafava A, Supuran CT (2000) Eur
J Pharm Sci 11:325
10. Bradshaw TD, Bibby MC, Double JA, Fichtner I, Cooper
PA, Alley MC, Donohue S, Stinson SF, Tomaszewjski JE,
Sausville EA, Stevens MFG (2002) Mol Cancer Ther
1:239
Methyl 2-{2-[2-(6-bromo-3-nitro-1H-indol-1-yl)-
acetamido]acetamido}acetate (29, C15H15BrN4O6)
Yellow foam (72%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 3.55 (s,
OCH3), 3.72 (s, CH2), 3.87 (s, CH2), 5.21 (s, N1-CH2), 7.45–
7.57 (m, Ar–H), 7.75 (s, H-2), 7.95 (s, H-7), 8.72 (br, s, NH)
ppm; MS (ESI): m=z ¼ 449=451 [Mþ þ Na].
(S)-Methyl 2-{2-[2-(6-bromo-3-nitro-1H-indol-1-yl)-
acetamido]acetamido}propanoate (30, C16H16BrN4O6)
Yellow foam (71%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 1.37 (d,
J ¼ 5.0 Hz, CH3), 3.63 (s, CH2), 3.70 (s, OCH3), 4.54 (q,
J ¼ 5.0 Hz, CH), 5.16 (s, N1-CH2), 7.45–7.60 (m, Ar–H),
7.79 (s, H-2), 7.96 (s, H-7), 8.88 (br, s, NH) ppm; MS
(ESI): m=z ¼ 463=465 [Mþ þ Na].
11. Brown DM, Horsman MR, Hirst DG, Brown GM (1984)
Int J Radiat Oncol Biol Phys 10:1665
12. a) Ali IAI, Al-Masoudi IA, Saeed B, Al-Masoudi NA, La
Colla P (2005) Heteroatom Chem 16:148; b) Al-Masoudi
NA, Al-Masoudi IA, Ali IAI, Al-Soud YA, Saeed B, La
Colla P (2006) Heteroatom Chem 16:576; c) Al-Masoudi
NA, Al-Masoudi IA, Ali IAI, Al-Soud YA, Saeed B, La
Colla P (2006) Acta Pharm 56:175; d) Ali IAI, Ali OM,
Abdel-Rahman AAH (2007) Monatsh Chem 138:909;
e) Ali OM, Abdel-Rahman AAH (2008) Monatsh Chem
139:53; f) Abdel-Rahman AAH (2008) Monatsh Chem
139:61
(S)-Methyl 2-{2-[2-(6-bromo-3-nitro-1H-indol-1-yl)-
acetamido]acetamido}-3-methylbutanoate
(31, C18H21BrN4O6)
Yellow foam (70%); 1H NMR (CDCl3, 250 MHz): ꢁ ¼ 0.98 (dd,
J ¼ 1.9, 7.3 Hz, 2ꢃCH3), 2.25–2.35 (m, CH), 3.66 (s, OCH3),
3.76 (s, CH2), 3.83 (s, CH2), 4.46–4.55 (m, CH), 5.16 (s,
N1-CH2), 7.45–7.56 (m, Ar–H), 7.75 (s, H-2), 7.90 (s, H-7),
8.94 (br, s, NH) ppm; MS (ESI): m=z ¼ 491=493 [Mþ þ Na].
13. Schwyzer R, Kappeler H (1961) Helv Chim Acta
44:1991
References
14. Janssen AM, Scheffer JJ, Svendsen AB (1986) Planta
Medica 395
1. Part VII: Abdel-Rahman AAH (2008) Monatsh Chem
139:289
15. Shaaban MT, El-Sharif ME (2001) Afr J Mycol Biotech-
nol 9(2):15
2. Somei M, Yamada F (2003) Nat Prod Rep 30:216
3. Hibino S, Chosi T (2002) Nat Prod Rep 19:148; 18:66